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Drug interactions with quinolones.
Numerous drug interactions with the new 4-quinolone antimicrobial agents have now been established. Many, but not all, quinolones are extensively metabolized and can have inhibitory effects on the liver cytochrome P450 enzyme system, leading to reduced metabolism and clearance of certain other drugs that are normally thus eliminated. Examples include the highly significant interaction between enoxacin and theophylline and the interaction between ciprofloxacin and theophylline, which may also be important clinically. The quinolone-caffeine interaction does not usually cause problems. Absorption of all quinolones from the stomach and small intestine is greatly reduced by antacids containing magnesium or aluminium salts, including sucralfate, probably as a result of the formation of nonabsorbable chelates. Cimetidine can reduce the clearance of pefloxacin (but not of ciprofloxacin) through its effects on liver metabolism, although newer H2-inhibitors appear not to have these effects. Probenecid reduces the renal elimination of some quinolones by inhibiting tubular secretion. New evidence is now coming to light of interactions between certain nonsteroid antiinflammatory drugs (e.g., fenbufen), quinolones, and gamma-aminobutyric acid (GABA) receptors, producing increased cerebral excitation and, sometimes, epileptiform convulsions. PMID:2570456
Davies, B I; Maesen, F P
On an aspect of calculated molecular descriptors in QSAR studies of quinolone antibacterials
SummaryĀĀThe re-emergence of tuberculosis infections, which are resistant to conventional drug therapy, has steadily risen in the last decade and as a result of that, fluoroquinolone drugs are being used as the second line of action. But there is hardly any study to examine specific structure activity relationships of quinolone antibacterials against mycobacteria. In this paper, an attempt has been
Payel Ghosh; Megha Thanadath; Manish C. Bagchi
Update on quinolone drug interactions.
Concurrent administration of both ciprofloxacin and norfloxacin with sucralfate leads to a decrease in quinolone bioavailability. It is unknown whether this decrease is clinically significant because studies have focused primarily on pharmacokinetics and not therapeutic outcomes. A reasonable recommendation may be to avoid using sucralfate and norfloxacin concurrently, or avoid administration of norfloxacin and ciprofloxacin within two hours of sucralfate administration. Magnesium- and aluminum-containing antacids may also interfere with quinolone absorption. Calcium carbonate and H2 receptor antagonists do not appear to interact with quinolones and may be considered as an alternative to sucralfate or magnesium- and aluminum-containing antacids when quinolones are administered. Concurrent administration of ciprofloxacin and theophylline may precipitate theophylline toxicity if not monitored carefully. Some clinicians recommend a 30% empiric reduction in theophylline dosage when ciprofloxacin therapy is initiated. Because the drug interaction is not completely predictable, the patient's theophylline levels should be monitored and signs and symptoms of toxicity noted, adjusting the dose as needed. Decreased theophylline clearance may persist for as long as five days following discontinuation of ciprofloxacin. Some potential for slight increases in serum theophylline concentrations secondary to norfloxacin administration may exist. However, it is unlikely to be clinically significant, based on currently available information. PMID:2220561
Hulisz, D; Miller, K
In vitro antibacterial activity of a new quinolone, NM394.
NM394 is a new 6-fluoroquinolone antibacterial agent with a tricyclic structure which has a bridge that connects the N-1 and C-2 positions of the quinolone. The antibacterial activity of NM394 against clinical isolates of staphylococci, streptococci, enterococci, members of the family Enterobacteriaceae, and Pseudomonas aeruginosa was equal to or one-half that of ciprofloxacin. NM394 was as active as ofloxacin against gram-positive bacteria and was two to eight times more active against gram-negative bacteria, including P. aeruginosa. NM394 was two to eight times more active than enoxacin against gram-positive and gram-negative bacteria. The MICs of NM394 against Escherichia coli and P. aeruginosa at pH 5.5 were reduced 4 to 16 times compared with those at pH 7.0. Ciprofloxacin, ofloxacin, and enoxacin were 2 to 32 times less active against these two bacteria and Staphylococcus aureus at an acidic pH than they were at pH 7.0. In the presence of 5 mM Mg2+, the MICs of all of these drugs increased 2 to 32 times, but they were only slightly affected by 5 mM Ca2+, type of medium, serum, or size of inoculum. NM394 showed potent bactericidal activity and inhibited the supercoiling activity of E. coli DNA gyrase. The in vitro antibacterial profile of NM394 is similar to that of other 6-fluoroquinolones. PMID:1667251
Ozaki, M; Matsuda, M; Tomii, Y; Kimura, K; Kazuno, K; Kitano, M; Kise, M; Shibata, K; Otsuki, M; Nishino, T
Design, synthesis, antibacterial evaluation and docking study of novel 2-hydroxy-3-(nitroimidazolyl)-propyl-derived quinolone.
A novel series of 2-hydroxy-3-(nitroimidazolyl)-propyl-derived quinolones 6a-o were synthesized and evaluated for their in vitro antibacterial activity. Most of the target compounds exhibited potent activity against Gram-positive strains. Among them, moxifloxacin analog 6n displayed the most potent activity against Gram-positive strains including S. epidermidis (MIC = 0.06 ?g/mL), MSSE (MIC = 0.125 ?g/mL), MRSE (MIC = 0.03 ?g/mL), S. aureus (MIC = 0.125 ?g/mL), MSSA (MIC = 0.125 ?g/mL), (MIC = 2 ?g/mL). Its activity against MRSA was eightfold more potent than reference drug gatifloxacin. Finally, docking study of the target compound 6n revealed that the binding model of quinolone nucleus was similar to that of gatifloxacin and the 2-hydroxy-3-(nitroimidazolyl)-propyl group formed two additional hydrogen bonds. PMID:25048811
Li, Qing; Xing, Junhao; Cheng, Haibo; Wang, Hui; Wang, Jing; Wang, Shuai; Zhou, Jinpei; Zhang, Huibin
Synthesis and in vitro antibacterial activity of quinolone/naphthyridone derivatives containing 3-alkoxyimino-4-(methyl)aminopiperidine scaffolds.
We report herein the synthesis of a series of 7-[3-alkoxyimino-4-(methyl)aminopiperidin-1-yl]quinolone/naphthyridone derivatives. In vitro antibacterial activity of these derivatives was evaluated against representative strains, and compared with ciprofloxacin (CPFX), levofloxacin (LVFX) and gemifloxacin (GMFX). The results reveal that all of the target compounds 19a-c and 20 have considerable Gram-positive activity, although they are generally less active than the reference drugs against the Gram-negative strains with some exceptions. Especially, novel compounds 19a2, 19a4 and 19a5 were found to show strong antibacterial activity (MICs: <0.008-0.5?g/mL) against all of the tested 15 Gram-positive strains including MRSA, LVFX- and GMFX-resistant MRSE, and CPFX-, LVFX- and GMFX-resistant MSSA. PMID:23402878
Lv, Kai; Wu, Jinwei; Wang, Jian; Liu, Mingliang; Wei, Zengquan; Cao, Jue; Sun, Yexin; Guo, Huiyuan
Mechanism of Quinolone Action and Resistance
Quinolones are one of the most commonly prescribed classes of antibacterials in the world and are used to treat a variety of bacterial infections in humans. Because of the wide use (and overuse) of these drugs, the number of quinolone-resistant bacterial strains has been growing steadily since the 1990s. As is the case with other antibacterial agents, the rise in quinolone resistance threatens the clinical utility of this important drug class. Quinolones act by converting their targets, gyrase and topoisomerase IV, into toxic enzymes that fragment the bacterial chromosome. This review describes the development of the quinolones as antibacterials, the structure and function of gyrase and topoisomerase IV, and the mechanistic basis for quinolone action against their enzyme targets. It will then discuss the following three mechanisms that decrease the sensitivity of bacterial cells to quinolones. Target-mediated resistance is the most common and clinically significant form of resistance. It is caused by specific mutations in gyrase and topoisomerase IV that weaken interactions between quinolones and these enzymes. Plasmid-mediated resistance results from extrachromosomal elements that encode proteins that disrupt quinolone¢enzyme interactions, alter drug metabolism, or increase quinolone efflux. Chromosome-mediated resistance results from the underexpression of porins or the overexpression of cellular efflux pumps, both of which decrease cellular concentrations of quinolones. Finally, this review will discuss recent advancements in our understanding of how quinolones interact with gyrase and topoisomerase IV and how mutations in these enzymes cause resistance. These last findings suggest approaches to designing new drugs that display improved activity against resistant strains. PMID:24576155
[Synthesis and antibacterial activity of 7-(3-amino-4-alkoxyimino-1 -piperidyl) -quinolones].
To explore new agents of quinolone derivatives with high activity against Gram-positive and Gram-negative microorganisms, 7-(3-amino-4-alkoxyimino-1-piperidyl) quinolones were designed and synthesized, and their activity against Gram-positive and Gram- negative microorganisms were tested in vivo and in vitro. Twenty one target compounds were obtained. Their structures were established by 1H NMR, HRMS and X-ray crystallographic analysis. The target compounds possess different antimicrobial activities against both Gram-negative and Gram-positive microorganisms. Compounds 14a and 14m have broad spectral antibacterial activities. They show better antibacterial activities against 12 strains Gram-positive bacteria than three references. In particular, their activities against S. aureus and S. epidermidis (including MRSA and MRSE) were 4 - 16 times than that of gemifloxacin and balofloxacin, and 8 - 64 times than that of levofloxacin. The MIC values to S. aureus strains of compounds 14a and 14m were 0.25 - 1 mg x L(-1) and 0.125 - 1 mg x L(-1), to S. epidermidis strains were 0.5 - 4 mg x L(-1) and 1 - 8 mg x L(-1) respectively. The in vivo results showed that they have as good internal protection as gemifloxacin and moxifloxacin against systemic infection model in mice (P > 0.05). PMID:18956774
Wang, Xiu-Yun; Guo, Qiang; Wang, Yu-Cheng; Liu, Bing-Quan; Liu, Ming-Liang; Sun, Lan-Ying; Guo, Hui-Yuan
Quinolones: a practical review of clinical uses, dosing considerations, and drug interactions.
A review of the literature on quinolones reveals numerous clinically relevant points regarding indications, dosing considerations, and drug interactions. Quinolones are useful in the treatment of several infectious diseases. Unfortunately, indiscriminate use of these valuable antimicrobials has resulted in increased patterns of resistance. It is important to consider carefully the site of infection and the potential pathogens in each patient before dosing. Quinolones have excellent oral absorption, with peak serum concentrations approaching those achieved with intravenous administration. When prescribing quinolones, the dose should be based on estimated creatinine clearance. Quinolones are associated with several clinically significant drug interactions. Some of these agents are well-documented inhibitors of hepatic metabolism of theophylline, caffeine, and warfarin. It has been well documented that divalent and trivalent cations in antacids, sucralfate, and some other products significantly reduce the absorption of quinolones. Avoidance or proper management of these interactions is required to ensure optimal safety and efficacy. PMID:8537808
Borcherding, S M; Stevens, R; Nicholas, R A; Corley, C R; Self, T
Antimicrobial use in Hungarian long-term care facilities: high proportion of quinolone antibacterials.
The aim of this survey was to estimate the burden of antimicrobial use and to describe the determinants for antimicrobial use in Hungarian long-term care facilities (LTCFs) in order to increase the attention given to the proper prescription for this vulnerable population. A one-day point-prevalence study was undertaken between April and May 2013. Data on resident treated with an antibacterial, antimycotic or tuberculostatic for systemic use were collected prospectively on a single day in each participating LTCF with over 50 beds. Descriptive statistics were used to present the data. 91 LTCFs with 11,823 residents participated in this survey. 156 residents (1.3%) were given antimicrobials. 96.8% of antimicrobials were mostly prescribed for therapy included urinary tract infections (40.3%), respiratory tract infections (38.4%) and skin and soft tissue infections (13.2%). The most common therapeutic antimicrobials (97.5%) belonged to the ATC J01 class of 'antibacterials for systemic use'. The most important J01 subclasses were J01M quinolone antibacterials (32.7%), J01C beta-lactam antibacterials (25.2%), J01D other beta-lactam antibacterials (11.3%) and J01F macrolides, lincosamides and streptogramins (11.3%). Antimicrobials were mostly prescribed empirically whereas 3.8% was microbiologically documented treatments. 3.2% of all prescribed antimicrobials were prescribed for the prophylaxis of urinary tract infections (60%) and ear, nose, mouth infections (40%). Our results emphasize the need of a national recommendation for good practice in LTCFs in order to avoid inappropriate antimicrobial therapy leading to spread of multidrug resistant pathogens. In addition, continuing education of prescribers on antimicrobial treatment is essential. PMID:24679670
Szab¾, Rita; B÷r÷cz, Karolina
Synthesis and in vitro antibacterial activity of 7-(4-alkoxyimino-3-methyl-3-methylaminopiperidin-1-yl)quinolones.
To explore new agents of quinolone derivatives with high antibacterial activity, 7-(4-alkoxyimino-3-methyl-3-methylaminopiperidin-1-yl)quinolones were designed and synthesized, and their activity against gram-positive and gram-negative strains was tested in vitro. Sixteen target compounds were obtained. Their structures were established by 1H NMR, HRMS and X-ray crystallographic analysis. Compounds 14k and 14m-14o show good antibacterial activity against the tested five gram-positive strains and five gram-negative strains (MIC: 0.25-16 micromg x mL(-1)), of which the most active compound 14o is 8-fold more potent than levofloxacin against S. pneumoniae (MIC: 4 microg x mL(-1)), and comparable to levofloxacin against S. aureus, S. epidermidis, E. faecalis and E. coli (MIC: 0.25-1 microg x mL(-1)), but generally less potent than gemifloxacin. PMID:20931783
Wan, Zhi-long; Chai, Yun; Liu, Ming-liang; Guo, Hui-yuan; Sun, Lan-ying
Definition of the heterocyclic pharmacophore of bacterial methionyl tRNA synthetase inhibitors: potent antibacterially active non-quinolone analogues
Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH¢C¢NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good
Richard L Jarvest; Sula A Armstrong; John M Berge; Pamela Brown; John S Elder; Murray J Brown; Royston C. B Copley; Andrew K Forrest; Dieter W Hamprecht; Peter J O'Hanlon; Darren J Mitchell; Stephen Rittenhouse; David R Witty
Recent advances in antibacterial drugs
The incidence of antimicrobial resistance is on continued rise with a threat to return to the ōpre-antibioticö era. This has led to emergence of such bacterial infections which are essentially untreatable by the current armamentarium of available treatment options. Various efforts have been made to develop the newer antimicrobials with novel modes of action which can act against these multi-drug resistant strains. This review aims to focus on these newly available and investigational antibacterials approved after year 2000, their mechanism of actions/resistance, and spectrum of activity and their phases of clinical trials. Newer unexploited targets and strategies for the next generation of antimicrobial drugs for combating the drug resistance and emerging pathogens in the 21st century have also been reviewed in the present article. PMID:23776832
Rai, Jaswant; Randhawa, Gurpreet Kaur; Kaur, Mandeep
Polyamidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: An in vitro study
Quinolones, an expanding class of clinically established potent antibiotics, is not freely soluble in water which prevents the design of liquid dosage forms and restricts their use in topical applications. In the present study we investigated the potential of polyamidoamine (PAMAM) dendrimers as drug carriers of quinolones (nadifloxacin and prulifloxacin) by aqueous solubility and antibacterial activity studies. Results showed that
Yiyun Cheng; Haiou Qu; Minglu Ma; Zhenhua Xu; Peng Xu; Yujie Fang; Tongwen Xu
Determination of fluorinated quinolone antibacterials by ion chromatography with fluorescence detection*
For preparing fluorinated quinolone antibiotic medicine locally used in stomatology, simultaneous determination of norfloxacin, ciprofloxacin, and enoxacin was carried out by multiphase ion chromatography with fluorescence detection. Quinolone antibiotics were separated by Dionex OmniPac PAX-500 column with an eluent of 15 mmol/L H2SO4 and 35% methanol (v/v) at a flow-rate of 1.0 ml/min and detected with fluorescence with excitation and emission wave lengths of 347 nm and 420 nm respectively. The detection limits (S/N=3) of norfloxacin, ciprofloxacin and enoxacin were 50, 105 and 80 ng/ml respectively. The relative standard deviations of retention time, peak area and peak height were less than 1.1% and good linear relationship resulted. The developed method was applied to pharmaceutical formulations and biological fluids. PMID:17542056
Zhang, Yan-zhen; Zhang, Zheng-yi; Zhou, Yan-chun; Liu, Li; Zhu, Yan
Fixed drug eruptions caused by cross-reactive quinolones
Fixed drug eruptions (FDE) are the common dermatological adverse drug reaction accounts for 16¢21% of all cutaneous drug reactions in India. Drugs most frequently implicated in FDE are antimicrobials, anticonvulsants, and nonsteroidal antiinflammatory drugs. Here, we report a rare case of bullous FDE due to ciprofloxacin followed by ofloxacin administration. PMID:25031501
Kameswari, P. Deepa; Selvaraj, Nitya; Adhimoolam, Mangaiarkkarasi
Antibacterial drug discovery: doing it right.
Antibacterial drug discovery needs to develop new strategies to identify attractive hit-target couples for more effective lead finding and optimization. In this issue of Chemistry & Biology, Park and coworkers describe a novel target-based whole cell combination screening approach resulting in the identification of new inhibitors of biotin biosynthesis in Mycobacterium tuberculosis. PMID:25615950
Gengenbacher, Martin; Dick, Thomas
Mechanism of action of and resistance to quinolones
Summary Fluoroquinolones are an important class of wide?spectrum antibacterial agents. The first quinolone described was nalidixic acid, which showed a narrow spectrum of activity. The evolution of quinolones to more potent molecules was based on changes at positions 1, 6, 7 and 8 of the chemical structure of nalidixic acid. Quinolones inhibit DNA gyrase and topoisomerase IV activities, two enzymes essential for bacteria viability. The acquisition of quinolone resistance is frequently related to (i) chromosomal mutations such as those in the genes encoding the A and B subunits of the protein targets (gyrA, gyrB, parC and parE), or mutations causing reduced drug accumulation, either by a decreased uptake or by an increased efflux, and (ii) quinolone resistance genes associated with plasmids have been also described, i.e. the qnr gene that encodes a pentapeptide, which blocks the action of quinolones on the DNA gyrase and topoisomerase IV; the aac(6?)?Ib?cr gene that encodes an acetylase that modifies the amino group of the piperazin ring of the fluoroquinolones and efflux pump encoded by the qepA gene that decreases intracellular drug levels. These plasmid?mediated mechanisms of resistance confer low levels of resistance but provide a favourable background in which selection of additional chromosomally encoded quinolone resistance mechanisms can occur. PMID:21261881
FÓbrega, Anna; Madurga, Sergi; Giralt, Ernest; Vila, Jordi
Drugs for bad bugs: confronting the challenges of antibacterial discovery
The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of
David J. Payne; Michael N. Gwynn; David J. Holmes; David L. Pompliano
UV-Vis Spectrophotometrical and Analytical Methodology for the Determination of Singlet Oxygen in New Antibacterials Drugs
We have determined and quantified spectrophotometrically the capacity of producing reactive oxygen species (ROS) as 1O2 during the photolysis with UV-A light of 5 new synthesized naphthyl ester derivates of well-known quinolone antibacterials (nalidixic acid (1), cinoxacin (2), norfloxacin (3), ciprofloxacin (4) and enoxacin (5)). The ability of the naphthyl ester derivatives (6¢10) to generate singlet oxygen were detecting and for the first time quantified by the histidine assay, a sensitive, fast and inexpensive method. The following tendency of generation of singlet oxygen was observed: compounds 7 > 10 > 6 > 8 > 9 >> parent drugs 1¢5. PMID:19662185
Zoltan, Tamara; Vargas, Franklin; Izzo, Carla
Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery.
The increase in drug-resistant pathogenic bacteria has created an urgent demand for new antibiotics. Among the more attractive targets for the development of new antibacterial compounds are the enzymes of fatty acid biosynthesis. Although a number of potent inhibitors of microbial fatty acid biosynthesis have been discovered, few of these are clinically useful drugs. Several of these fatty acid biosynthesis inhibitors have potential as lead compounds in the development of new antibacterials. This review encompasses the known inhibitors and prospective targets for new antibacterials. PMID:11544358
Campbell, J W; Cronan, J E
Functional Analysis of Pneumococcal Drug Efflux Pumps Associates the MATE DinF Transporter with Quinolone Susceptibility
The pneumococcal chromosome encodes about 140 transporters, many of which are predicted to be involved in efflux. In order to critically evaluate pneumococcal efflux, a series of transporter mutants were constructed, and their phenotypes were assayed by disk diffusion, microdilution drug susceptibility testing (MIC testing), growth of cultures at sub-MIC concentrations, and phenotype microarray analysis. Mutants with mutations in seven ATP binding cassette (ABC) transporters, three multiantimicrobial extrusion (MATE) family efflux pumps, and one major facilitator superfamily (MFS) transporter were obtained in Streptococcus pneumoniae strain DP1004. The susceptibility of these 11 mutants to over 250 different substances was compared to that of the parent strain. Of the tested transporters, only the ABC transporter PatAB (SP2073-5) presented a clear multidrug resistance (MDR) profile, as the mutant showed significantly increased susceptibility to ethidium bromide, acriflavine, and berberine. Among the other transporters analyzed, the mutants devoid of the MATE efflux pump SP2065 exhibited reduced susceptibility to novobiocin, and those with mutations of the MATE family DinF transport system (SP1939) exhibited increased susceptibility to moxifloxacin, ciprofloxacin, and levofloxacin. This change in quinolone MIC was found to be independent from the competence-mediated effect of quinolones on the cinA-recA-dinF operon. Furthermore, the dinF mutant, in contrast to the parental strain, allowed selection for quinolone-resistant mutants when exposed to moxifloxacin. These data confirm the clear MDR profile of the PatAB ABC transporter and suggest for the MATE DinF a phenotype associated with quinolone susceptibility, particularly for moxifloxacin. PMID:23114782
Tocci, Nadia; Iannelli, Francesco; Bidossi, Alessandro; Ciusa, Maria Laura; Decorosi, Francesca; Viti, Carlo; Pozzi, Gianni; Ricci, Susanna
Cost-effectiveness and Pricing of Antibacterial Drugs
Growing resistance to antibacterial agents has increased the need for the development of new drugs to treat bacterial infections. Given increasing pressure on limited health budgets, it is important to study the cost-effectiveness of these drugs, as well as their safety and efficacy, to find out whether or not they provide value for money and should be reimbursed. In this article, we systematically reviewed 38 cost-effectiveness analyses of new antibacterial agents. Most studies showed the new antibacterial drugs were cost-effective compared to older generation drugs. Drug pricing is a complicated process, involving different stakeholders, and has a large influence on cost-effectiveness. Value-based pricing is a method to determine the price of a drug at which it can be cost-effective. It is currently unclear what the influence of value-based pricing will be on the prices of new antibacterial agents, but an important factor will be the definition of ævalueÆ, which as well as the impact of the drug on patient health might also include other factors such as wider social impact and the health impact of disease. PMID:25521641
Verhoef, Talitha I; Morris, Stephen
Cost-effectiveness and pricing of antibacterial drugs.
Growing resistance to antibacterial agents has increased the need for the development of new drugs to treat bacterial infections. Given increasing pressure on limited health budgets, it is important to study the cost-effectiveness of these drugs, as well as their safety and efficacy, to find out whether or not they provide value for money and should be reimbursed. In this article, we systematically reviewed 38 cost-effectiveness analyses of new antibacterial agents. Most studies showed the new antibacterial drugs were cost-effective compared to older generation drugs. Drug pricing is a complicated process, involving different stakeholders, and has a large influence on cost-effectiveness. Value-based pricing is a method to determine the price of a drug at which it can be cost-effective. It is currently unclear what the influence of value-based pricing will be on the prices of new antibacterial agents, but an important factor will be the definition of 'value', which as well as the impact of the drug on patient health might also include other factors such as wider social impact and the health impact of disease. PMID:25521641
Verhoef, Talitha I; Morris, Stephen
Innovative approaches to novel antibacterial drug discovery
Increasing antibiotic resistance in microorganisms and new emerging pathogens have become a major problem in our society. Rising to satisfy this urgent medical need is a recent confluence of powerful new drug discovery technologies: combinatorial chemistry; sequence and functional genomic analysis; and novel methods of high-throughput screening. The combination of these technologies will bring to bear untapped power in the
Joaquim Trias; Eric M Gordon
Undecaprenyl diphosphate synthase inhibitors: antibacterial drug leads.
There is a significant need for new antibiotics due to the rise in drug resistance. Drugs such as methicillin and vancomycin target bacterial cell wall biosynthesis, but methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) have now arisen and are of major concern. Inhibitors acting on new targets in cell wall biosynthesis are thus of particular interest since they might also restore sensitivity to existing drugs, and the cis-prenyl transferase undecaprenyl diphosphate synthase (UPPS), essential for lipid I, lipid II, and thus, peptidoglycan biosynthesis, is one such target. We used 12 UPPS crystal structures to validate virtual screening models and then assayed 100 virtual hits (from 450,000 compounds) against UPPS from S. aureus and Escherichia coli. The most promising inhibitors (IC50 ?2 ?M, Ki ?300 nM) had activity against MRSA, Listeria monocytogenes, Bacillus anthracis, and a vancomycin-resistant Enterococcus sp. with MIC or IC50 values in the 0.25-4 ?g/mL range. Moreover, one compound (1), a rhodanine with close structural similarity to the commercial diabetes drug epalrestat, exhibited good activity as well as a fractional inhibitory concentration index (FICI) of 0.1 with methicillin against the community-acquired MRSA USA300 strain, indicating strong synergism. PMID:24827744
Sinko, William; Wang, Yang; Zhu, Wei; Zhang, Yonghui; Feixas, Ferran; Cox, Courtney L; Mitchell, Douglas A; Oldfield, Eric; McCammon, J Andrew
Preparation, structure and microbial evaluation of metal complexes of the second generation quinolone antibacterial drug lomefloxacin
NASA Astrophysics Data System (ADS)
Lomefloxacinate of Y(III), Zr(IV) and U(VI) were isolated as solids with the general formula; [Y(LFX) 2Cl 2]ClĘ12H 2O, [ZrO(LFX) 2Cl]ClĘ15H 2O and [UO 2(LFX) 3](NO 3) 2Ę4H 2O. The new synthesized complexes were characterized with physicochemical and diverse spectroscopic techniques (IR, UV-Vis. and 1H NMR spectroscopies) as well as thermal analyses. In these complexes lomefloxacin act as bidentate ligand bound to the metal ions through the pyridone oxygen and one carboxylate oxygen. The kinetic parameters of thermogravimetric (TGA) and its differential (DTG), such as entropy of activation, activation energy, enthalpy of activation and Gibbs free energy evaluated by using Coats- Redfern and Horowitz- Metzger equations for free lomefloxacin and three complexes were carried out. The bond stretching force constant and length of the U dbnd O bond for the [UO 2(LFX) 3](NO 3) 2Ę4H 2O complex were calculated. The antimicrobial activity of lomefloxacin and its metal complexes was tested against different bacterial species, such as Staphylococcus aureus ( S. aureus), Escherichia coli ( E. coli) and Pseudomonas aeruginosa ( P. aeruginosa) as Gram-positive and Gram-negative bacterial species and also against two species of antifungal, penicillium ( P. rotatum) and trichoderma ( T. sp.). The three complexes are of a good action against three bacterial species but the Y(III) complex exhibit excellent activity against Pseudomonas aeruginosa ( P. aeruginosa), when compared to the free lomefloxacin.
Sadeek, Sadeek A.; El-Shwiniy, Walaa H.
7-(4-Alkylidenylpiperidinyl)-quinolone bacterial topoisomerase inhibitors.
Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7-position substituent are active against quinolone-susceptible and quinolone-resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci. PMID:25455493
Grant, Eugene B; Foleno, Barbara D; Goldschmidt, Raul; Hilliard, Jamese J; Lin, Shu-Chen; Morrow, Brian; Paget, Steven D; Weidner-Wells, Michele A; Xu, Xiaodong; Xu, Xiaoqing; Murray, William V; Bush, Karen; Macielag, Mark J
Metal complexes of the fourth generation quinolone antimicrobial drug gatifloxacin: Synthesis, structure and biological evaluation
NASA Astrophysics Data System (ADS)
Three metal complexes of the fourth generation quinolone antimicrobial agent gatifloxacin (GFLX) with Y(???), Zr(?V) and U(V?) have been prepared and characterized with physicochemical and spectroscopic techniques. In these complexes, gatifloxacin acts as a bidentate deprotonated ligand bound to the metal through the ketone oxygen and a carboxylato oxygen. The complexes are six-coordinated with distorted octahedral geometry. The kinetic parameters for gatifloxacin and the three prepared complexes have been evaluated from TGA curves by using Coats-Redfern (CR) and Horowitz-Metzeger (HM) methods. The calculated bond length and force constant, F(U dbnd O), for the UO 2 bond in uranyl complex are 1.7522 ┼ and 639.46 N m -1. The antimicrobial activity of the complexes has been tested against microorganisms, three bacterial species, such as Staphylococcus aureus ( S. aureus), Escherichia coli ( E. coli) and Pseudomonas aeruginosa ( P. aeruginosa) and two fungi species, penicillium ( P. rotatum) and trichoderma ( T. sp.), showing that they exhibit higher activity than free ligand.
Sadeek, Sadeek A.; El-Shwiniy, Walaa H.
77 FR 49450 - Issues in the Design of Clinical Trials of Antibacterial Drugs for the Treatment of Non-Cystic...
Federal Register 2010, 2011, 2012, 2013, 2014
...of Antibacterial Drugs for the Treatment of Non-Cystic Fibrosis Bronchiectasis; Public Workshop AGENCY: Food and...of antibacterial drugs for the treatment of non-cystic fibrosis (non-CF) bronchiectasis. This public...
Quality assessment of drug sales data: the case of antibacterials in Iceland
Background: Two sets of drug sales data, published by the Icelandic Ministry of Health, did not match for antibacterials in 1989. The search for causes turned out to be a project in itself. Objective: To analyze quality problems in the sales data on antibacterials and describe a method for systematic quality assessment of drug sales data. Methods: Documentary analysis based
Ingunn Bj÷rnsd¾ttir; Ebba Holme Hansen; Almar GrĒmsson
Newer Antibacterials in Therapy and Clinical Trials
In order to deal with the rising problem of antibiotic resistance, newer antibacterials are being discovered and added to existing pool. Since the year 2000, however, only four new classes of antibacterials have been discovered. These include the oxazolidinones, glycolipopeptides, glycolipodepepsipeptide and pleuromutilins. Newer drugs were added to existing classes of antibiotics, such as streptogramins, quinolones, beta-lactam antibiotics, and macrolide-, tetracycline- and trimethoprim-related drugs. Most of the antibacterials are directed against resistant S. aureus infections, with very few against resistant gram-negative infections. The following article reviews the antibacterials approved by the FDA after the year 2000 as well as some of those in clinical trials. Data was obtained through a literature search via Pubmed and google as well as a detailed search of our library database. PMID:23181224
Paknikar, Simi S; Narayana, Sarala
Accelerating resistance, inadequate antibacterial drug pipelines and international responses.
The pandemic of multidrug-resistant (MDR) pathogens and their continuing spread is beyond dispute. In contrast to the past, today's antibacterial research and development (R&D) pipelines are nearly dry, failing to provide the flow of novel antibiotics required to match the clinical challenges of the multidrug resistance (MDR) crisis. Concerned over the rapidly worsening potential global healthcare crisis caused by MDR bacteria and the lack of robust drug pipelines, several multinational campaigns have issued policy recommendations and have initiated broad discussion with a goal of stimulating the development of novel antibacterial drugs and technologies. These activities have resulted in intensified co-operation between the USA and the EU. The recently announced extensive 'Action plan against the rising threats from antimicrobial resistance' substantially ramps up action within the EU. In recognising the potential crisis caused by MDR and the limited treatment options, the European Commission decided on an unprecedented approach to drive the search for novel antibiotics by integrating the pharmaceutical industry, the research capacities of universities and small companies supported by public funding along with pricing/reimbursement and regulatory bodies. The European Commission has shown leadership and put action plans in place. Only the future will tell whether these initiatives will help curb the impact of the MDR pandemic. PMID:22341298
Theuretzbacher, Ursula
Conjugation between quinolone-susceptible bacteria can generate mutations in the quinolone resistance-determining region, inducing quinolone resistance.
Quinolones are an important group of antibacterial agents that can inhibit DNA gyrase and topoisomerase IV activity. DNA gyrase is responsible for maintaining bacteria in a negatively supercoiled state, being composed of subunits A and B. Topoisomerase IV is a homologue of DNA gyrase and consists of two subunits codified by the parC and parE genes. Mutations in gyrA and gyrB of DNA gyrase may confer resistance to quinolones, and the majority of resistant strains show mutations between positions 67 and 106 of gyrA, a region denoted the quinolone resistance-determining region (QRDR). The most frequent substitutions occur at positions 83 and 87, but little is known about the mechanisms promoting appearance of mutations in the QRDR. The present study proposes that some mutations in the QRDR could be generated as a result of the natural mechanism of conjugation between bacteria in their natural habitat. This event was observed following conjugation in vitro of two different isolates of quinolone-susceptible Pseudomonas aeruginosa, which transferred plasmids of different molecular weights to a recipient strain of Escherichia coli (HB101), also quinolone-susceptible, generating two different transconjugants that presented mutations in DNA gyrase and acquisition of resistance to all quinolones tested. PMID:25262036
Pitondo-Silva, Andrķ; Martins, Vinicius Vicente; Silva, Carolina Fßvero da; Stehling, Eliana Guedes
DRUG DISCOVERY AND RESISTANCE Antibacterial activities of dendritic amphiphiles against nontuberculous
DRUG DISCOVERY AND RESISTANCE Antibacterial activities of dendritic amphiphiles against November 2011 Accepted 4 December 2011 Keywords: Dendritic amphiphiles Nontuberculous mycobacteria Anti of nine series of dicarboxyl and tricarboxyl dendritic amphiphiles with one alkyl, two alkyl
Falkinham, Joseph
Genetic analysis of a pediatric clinical isolate of Moraxella catarrhalis with resistance to macrolides and quinolones.
During the surveillance conducted in 2012 by the Drug-resistant Pathogen Surveillance Group in Pediatric Infectious Disease, we isolated a strain of Moraxella catarrhalis that demonstrated resistance to both macrolides and quinolones from a male pediatric patient aged 1.5 years who had developed acute bronchitis. Then we evaluated the susceptibility of this strain to different types of antibacterial agents and conducted a genetic analysis. The results of the susceptibility evaluation showed that the MIC values of azithromycin, clarithromycin, and rokitamycin were >64Ā?g/mL, >64Ā?g/mL, and 4Ā?g/mL, respectively; clearly demonstrating resistance to macrolides. The MIC values of the quinolones levofloxacin, tosufloxacin, and garenoxacin were 4Ā?g/mL, 2Ā?g/mL, and 1Ā?g/mL, respectively; indicating decreased susceptibility. The genetic analysis of this strain revealed one mutation in 23s rRNA with a replacement of adenine by thymine at nucleotide position 2330 (A2330T) and another mutation in gyrB at nucleotide position 1481 by replacement of adenine with guanine (A1481G) that caused a substitution of the 494th asparagine acid by glycine, as being associated with the observed resistance to macrolides and quinolones, respectively. Similar to drug-resistant bacteria Streptococcus pneumoniae and Haemophilus influenzae, the prevalence of which has recently increased, the treatment of drug-resistant M. catarrhalis infections is considered difficult due to the development of resistance to different types of antibacterial agents. It is vital to maintain an unwavering focus on the trend toward an increasing number of drug-resistant M. catarrhalis strains and ensure the proper use of each antibacterial agent. PMID:25481761
Iwata, Satoshi; Sato, Yoshitake; Toyonaga, Yoshikiyo; Hanaki, Hideaki; Sunakawa, Keisuke
Discovery of new antitumoral and antibacterial drugs from brazilian plant extracts using high throughput screening
Plants have played a significant role in the treatment of cancer and infectious diseases for the last four decades. The discovery and introduction to market of paclitaxel, the vinca alkaloids, etoposide, and many antibacterial drugs support drug discovery programs based on natural products. Natural products have been rediscovered as important tools for drug development despite advances in combinatorial chemistry, due
Riad Naim Younes; Antonio Drauzio Varella; Ivana Barbosa Suffredini
The promise of riboswitches as potential antibacterial drug targets.
Riboswitches represent promising novel RNA structures for developing compounds that artificially regulate gene expression and, thus, bacterial growth. The past years have seen increasing efforts to identify metabolite-analogues which act on riboswitches and which reveal antibacterial activity. Here, we summarize the current inventory of riboswitch-targeting compounds, their characteristics and antibacterial potential. PMID:24140145
L³nse, Christina E; Sch³ller, Anna; Mayer, G³nter
Bacterial histidine kinases as novel antibacterial drug targets.
Bacterial histidine kinases (HKs) are promising targets for novel antibacterials. Bacterial HKs are part of bacterial two-component systems (TCSs), the main signal transduction pathways in bacteria, regulating various processes including virulence, secretion systems and antibiotic resistance. In this review, we discuss the biological importance of TCSs and bacterial HKs for the discovery of novel antibacterials, as well as published TCS and HK inhibitors that can be used as a starting point for structure-based approaches to develop novel antibacterials. PMID:25436989
Bem, Agnieszka E; Velikova, Nadya; Pellicer, M Teresa; Baarlen, Peter van; Marina, Alberto; Wells, Jerry M
Antiplasmodial drugs in the gas phase: a CID and DFT study of quinolon-4(1H)-imine derivatives.
The gas-phase behavior of 12 quinolon-4(1H)-imine derivatives with antiplasmodial activity was investigated using electrospray ionization tandem mass spectrometry together with collision induced dissociation and density functional theory (DFT) calculations. The most probable protonation site was predicted by calculating the proton affinity (PA) values for each possible protonation site and it was found to be the imine nitrogen for all compounds under study. Fragmentation pathways of the protonated molecules were proposed and the assignment of product ion structures was performed taking into account theoretical calculations. The nature of the quinoline substituent was found to influence the gas-phase behavior of the compounds under study. The data acquired allowed to bracket the proton affinity of the quinolin-4-imine scaffold, which can be a useful starting point to choose appropriate references for determining PA values of this scaffold. PMID:25001380
Amorim Madeira, Paulo J; Sitoe, Ana Raquel Fernandes; Gonńalves, Daniel; Rodrigues, Tiago; Guedes, Rita C; Lopes, Francisca; Moreira, Rui; Bronze, M Rosßrio
Antiplasmodial Drugs in the Gas Phase: A CID and DFT Study of Quinolon-4( 1H)-Imine Derivatives
NASA Astrophysics Data System (ADS)
The gas-phase behavior of 12 quinolon-4( 1H)-imine derivatives with antiplasmodial activity was investigated using electrospray ionization tandem mass spectrometry together with collision induced dissociation and density functional theory (DFT) calculations. The most probable protonation site was predicted by calculating the proton affinity (PA) values for each possible protonation site and it was found to be the imine nitrogen for all compounds under study. Fragmentation pathways of the protonated molecules were proposed and the assignment of product ion structures was performed taking into account theoretical calculations. The nature of the quinoline substituent was found to influence the gas-phase behavior of the compounds under study. The data acquired allowed to bracket the proton affinity of the quinolin-4-imine scaffold, which can be a useful starting point to choose appropriate references for determining PA values of this scaffold.
Amorim Madeira, Paulo J.; Sitoe, Ana Raquel Fernandes; Gonńalves, Daniel; Rodrigues, Tiago; Guedes, Rita C.; Lopes, Francisca; Moreira, Rui; Bronze, M. Rosßrio
Synthesis, characterization, antibacterial activity, SOD mimic and interaction with DNA of drug based copper(II) complexes
NASA Astrophysics Data System (ADS)
Novel metal complexes of the second-generation quinolone antibacterial agent enrofloxacin with copper(II) and neutral bidentate ligands have been prepared and characterized with elemental analysis reflectance, IR and mass spectroscopy. Complexes have been screened for their in-vitro antibacterial activity against two Gram (+ve)Staphylococcus aureus, Bacillus subtilis, and three Gram (-ve)Serratia marcescens, Escherichia coli and Pseudomonas aeruginosa organisms using the double dilution technique. The binding of this complex with CT-DNA has been investigated by absorption titration, salt effect and viscosity measurements. Binding constant is ranging from 1.3 ū 10 4-3.7 ū 10 4. The cleavage ability of complexes has been assessed by gel electrophoresis using pUC19 DNA. The catalytic activity of the copper(II) complexes towards the superoxide anion (O 2rad -) dismutation was assayed by their ability to inhibit the reduction of nitroblue tetrazolium (NBT).
Patel, Mohan N.; Dosi, Promise A.; Bhatt, Bhupesh S.; Thakkar, Vasudev R.
21 CFR 201.24 - Labeling for systemic antibacterial drug products.
Code of Federal Regulations, 2010 CFR
...to treat or prevent infections that are proven or strongly suspected to be caused by...to treat or prevent infections that are proven or strongly suspected to be caused...antibacterial drug product ) in the absence of a proven or strongly suspected bacterial...
Impact of antibacterial drugs on human serum paraoxonase-1 (hPON1) activity: an in vitro study
Objective To investigate the in vitro effects of the antibacterial drugs, meropenem trihydrate, piperacillin sodium, and cefoperazone sodium, on the activity of human serum paraoxonase (hPON1). Methods hPON1 was purified from human serum using simple chromatographic methods, including DEAE-Sephadex anion exchange and Sephadex G-200 gel filtration chromatography. Results The three antibacterial drugs decreased in vitro hPON1 activity. Inhibition mechanisms meropenem trihydrate was noncompetitive while piperacillin sodium and cefoperazone sodium were competitive. Conclusions Our results showed that antibacterial drugs significantly inhibit hPON1 activity, both in vitro, with rank order meropenem trihydrate piperacillin sodium cefoperazone sodium in vitro. PMID:25183328
S÷y³t, Hakan; Kaya, Elif Duygu; Beydemir, ?³kr³
The quinolones: decades of development and use
The discovery of nalidixic acid in 1962, and its introduction for clinical use in 1967, marks the beginning of five decades of quinolone development and use. It was not until the discovery and licensing of the fluoroquinolones in the 1970s and 1980s that these drugs began to establish their place in the armamentarium of clinically useful antimicrobials. At the beginning
A. M. Emmerson; A. M. Jones
Antitubercular and antibacterial activity of quinonoid natural products against multi-drug resistant clinical isolates.
Multi-drug resistant Mycobacterium tuberculosis and other bacterial pathogens represent a major threat to human health. In view of the critical need to augment the current drug regime, we have investigated therapeutic potential of five quinonoids, viz. emodin, diospyrin, plumbagin, menadione and thymoquinone, derived from natural products. The antimicrobial activity of quinonoids was evaluated against a broad panel of multi-drug and extensively drug-resistant tuberculosis (M/XDR-TB) strains, rapid growing mycobacteria and other bacterial isolates, some of which were producers of ?-lactamase, Extended-spectrum ?-lactamase (ESBL), AmpC ?-lactamase, metallo-beta-lactamase (MBL) enzymes, as well as their drug-sensitive ATCC counterparts. All the tested quinones exhibited antimycobacterial and broad spectrum antibacterial activity, particularly against M. tuberculosis (lowest MIC 0.25?Ąg/mL) and Gram-positive bacteria (lowest MIC <4?Ąg/mL) of clinical origin. The order of antitubercular activity of the tested quinonoids was plumbagin?>?emodin?~?menadione?~?thymoquinone?>?diospyrin, whereas their antibacterial efficacy was plumbagin?>?menadione?~?thymoquinone?>?diospyrin?>?emodin. Furthermore, this is the first evaluation performed on these quinonoids against a broad panel of drug-resistant and drug-sensitive clinical isolates, to the best of our knowledge. PMID:24318724
Dey, Diganta; Ray, Ratnamala; Hazra, Banasri
Antibacterial drugs as corrosion inhibitors for bronze surfaces in acidic solutions
NASA Astrophysics Data System (ADS)
The present study is aiming to investigate the effect of four antibiotics (amoxicillin, ciprofloxacin, doxycycline and streptomycin,) belonging to different classes of antibacterial drugs on bronze corrosion in a solution simulating an acid rain (pH 4). Due to their ability to form protective films on the metal surface, the tested antibiotics act as corrosion inhibitors for bronze. The antibiotics were tested at various concentrations in order to determine the optimal concentration range for the best corrosion inhibiting effect. In evaluating the inhibition efficiency, polarization curves, electrochemical impedance spectroscopy, SEM and XPS measurements were used. Moreover, a correlation between the inhibition efficiency of some antibacterial drugs and certain molecular parameters was determined by quantum chemical computations. Parameters like energies EHOMO and ELUMO and HOMO-LUMO energy gap were used for correlation with the corrosion data.
Rotaru, Ileana; Varvara, Simona; Gaina, Luiza; Muresan, Liana Maria
Antibacterial drugs as inhibitors for the corrosion of stainless steel type 304 in HCl solution
The effect of three antibacterial drugs (3-thiazinonyl-bicyclo [4.2.0] octene-carboxylate derivatives) on the corrosion behavior\\u000a of stainless steel type 304 in 1.0ĀM HCl solution has been investigated using weight loss, potentiodynamic polarization, and\\u000a electrochemical impedance spectroscopy (EIS) techniques. The inhibition efficiency increased with increase in inhibitor concentration\\u000a but decreased with increase in temperature. The thermodynamic functions of corrosion and adsorption processes
A. S. Fouda; H. A. Mostafa; H. M. El-Abbasy
Comparative Genomic Assessment of Novel Broad-Spectrum Targets for Antibacterial Drugs
Single and multiple resistance to antibacterial drugs currently in use is spreading, since they act against only a very small number of molecular targets; finding novel targets for anti-infectives is therefore of great importance. All protein sequences from three pathogens (Staphylococcus aureus, Mycobacterium tuberculosis and Escherichia coli O157:H7 EDL993) were assessed via comparative genomics methods for their suitability as antibacterial targets according to a number of criteria, including the essentiality of the protein, its level of sequence conservation, and its distribution in pathogens, bacteria and eukaryotes (especially humans). Each protein was scored and ranked based on weighted variants of these criteria in order to prioritize proteins as potential novel broad-spectrum targets for antibacterial drugs. A number of proteins proved to score highly in all three species and were robust to variations in the scoring system used. Sensitivity analysis indicated the quantitative contribution of each metric to the overall score. After further analysis of these targets, tRNA methyltransferase (trmD) and translation initiation factor IF-1 (infA) emerged as potential and novel antimicrobial targets very worthy of further investigation. The scoring strategy used might be of value in other areas of post-genomic drug discovery. PMID:18629165
White, Thomas A.
Novel antibacterials: a genomics approach to drug discovery.
The appearance of antibiotic resistant pathogens, including vancomycin resistant Staphylococcus aureus, in the clinic has necessitated the development of new antibiotics. The golden age of antibiotic discovery, in which potent selective compounds were readily extracted from natural product extracts is over and novel approaches need to be implemented to cover the therapeutic shortfall. The generation of huge quantities of bacterial sequence data has allowed the identification of all the possible targets for therapeutic intervention and allowed the development of screens to identify inhibitors. Here, we described a number of target classes in which genomics has contributed to its identification. As a result of analyzing sequence data, all of the tRNA synthetases and all of the two-component signal transduction systems were readily isolated; which would not have been easily identified if whole genome sequences were not available. Fatty acid biosynthesis is a known antibacterial target, but genomics showed which genes in that pathway had the appropriate spectrum to be considered as therapeutic targets. Genes of unknown function may seem untractable targets, but if those that are broad spectrum and essential are identified, it becomes valuable to invest time and effort to determine their cellular role. In addition, we discuss the role of genomics in developing technologies that assist in the discovery of new antibiotics including microarray gridding technology. Genomics can also increase the chemical diversity against which the novel targets can be screened. PMID:12570737
Chan, Pan F; Macarron, Ricardo; Payne, David J; Zalacain, Magdalena; Holmes, David J
FROM THE ANALYST'S COUCH The antibacterial drugs market
Rovini `LCP Chaise' courtesy of the MoMA Design Store www.momastore.org The pharmaceutical industry owes lifecycles increases the risk to drug developers (as they have less time to recoup their R&D investments for intensive lifecycle-management strategies (for example, developing an extended-release formulation). All
Cai, Long
Microbial geneticsGenetic strategies for antibacterial drug discovery
The availability of genome sequences is revolutionizing the field of microbiology. Genetic methods are being modified to facilitate rapid analysis at a genome-wide level and are blossoming for human pathogens that were previously considered intractable. This revolution coincided with a growing concern about the emergence of microbial drug resistance, compelling the pharmaceutical industry to search for new antimicrobial agents. The
Jonathan Greene; Todd A. Black; Lynn Miesel
Machine-learning techniques applied to antibacterial drug discovery.
The emergence of drug-resistant bacteria threatens to revert humanity back to the preantibiotic era. Even now, multidrug-resistant bacterial infections annually result in millions of hospital days, billions in healthcare costs, and, most importantly, tens of thousands of lives lost. As many pharmaceutical companies have abandoned antibiotic development in search of more lucrative therapeutics, academic researchers are uniquely positioned to fill the pipeline. Traditional high-throughput screens and lead-optimization efforts are expensive and labor intensive. Computer-aided drug-discovery techniques, which are cheaper and faster, can accelerate the identification of novel antibiotics, leading to improved hit rates and faster transitions to preclinical and clinical testing. The current review describes two machine-learning techniques, neural networks and decision trees, that have been used to identify experimentally validated antibiotics. We conclude by describing the future directions of this exciting field. PMID:25521642
Durrant, Jacob D; Amaro, Rommie E
Investigation of Smith's quinolone killing mechanisms during the PAE of ciprofloxacin on Escherichia coli.
Quinolone antibacterials interact with the DNA-DNA gyrase complex, but subsequent events that lead to cell death are unresolved. Three distinct mechanisms of quinolone lethality have been identified by Smith and co-workers: Mechanism A, which requires RNA and protein synthesis and cell division for expression; Mechanism B, which remains active when these functions are precluded; and Mechanism C, which is active on non-dividing cells. Exposure to 4x MIC ciprofloxacin (Cip) in nutrient broth (NB) for 3 h reduced the viability of Escherichia coli AB1157 to 0.25%. Addition of rifampicin (Rif) or chloramphenicol (Cm), to inhibit RNA or protein synthesis, respectively, increased survival 70-fold. Treatment of cells with Cip in phosphate-buffered saline (PBS), to inhibit cell division, increased survival 20-fold. No further cell death occurred once the various drug combinations or PBS had been washed out and cells resuspended in drug-free nutrient broth. These latter conditions allow expression of the post-antibiotic effect (PAE). PAE was lengthened in cells exposed to Cip in the presence of Rif or Cm, probably as a result of delay in the initiation of inducible DNA repair. PMID:11564549
Wickens, H J; Pinney, R J
Peptide deformylase: a new target in antibacterial, antimalarial and anticancer drug discovery.
Peptide deformylase (PDF) is a class of metalloenzyme responsible for catalyzing the removal of the N-formyl group from N-terminal methionine following translation. PDF inhibitors are moving into new phase of drug development. Initially, PDF was considered as an important target in antibacterial drug discovery; however genome database searches have revealed PDF-like sequences in parasites (P. falciparum) and human, widening the utility of this target in antimalarial and anticancer drug discovery along with antibacterial. Using structural and mechanistic information together with high throughput screening, several types of chemical classes of PDF inhibitors with improved efficacy and specificity have been identified. Various drugs like, GSK-1322322 (Phase II), BB-83698 (Phase I), and LBM-415 (Phase I) have entered into clinical developments. Developments in the field have prompted us to review the current aspects of PDFs, especially their structures, different classes of PDF inhibitors, and molecular modeling studies. In nut shell, this review enlightens PDF as a versatile target along with its inhibitors and future perspectives of different PDF inhibitors. PMID:25174923
Sangshetti, Jaiprakash N; Khan, Firoz A Kalam; Shinde, Devanand B
Quinolone-Containing Therapies in the Eradication of Helicobacter pylori
Fluoroquinolones, especially levofloxacin, are used in the eradication of Helicobacter pylori worldwide. Many consensus guidelines recommend that the second-line rescue therapy for H. pylori eradication consists of a proton pump inhibitor, a quinolone, and amoxicillin as an option. Unfortunately, quinolone is well associated with a risk of developing bacterial resistance. In this paper, we review quinolone-containing H. pylori eradication regimens and the challenges that influence the efficacy of eradication. It is generally suggested that the use of levofloxacin should be confined to ōrescueö therapy only, in order to avoid a further rapid increase in the resistance of H. pylori to quinolone. The impact of quinolone-containing H. pylori eradication regimens on public health issues such as tuberculosis treatment must always be taken into account. Exposure to quinolone is relevant to delays in diagnosing tuberculosis and the development of drug resistance. Extending the duration of treatment to 14 days improves eradication rates by >90%. Tailored therapy to detect fluoroquinolone-resistant strains can be done by culture-based and molecular methods to provide better eradication rates. Molecular methods are achieved by using a real-time polymerase chain reaction to detect the presence of a gyrA mutation, which is predictive of treatment failure with quinolones-containing triple therapy. PMID:25243116
Tai, Wei-Chen; Lee, Chen-Hsiang; Liang, Chih-Ming; Hu, Tsung-Hui
The usage of veterinary antibacterial drugs for mastitis in cattle in Norway and Sweden during 1990¢1997
The prescribing patterns and annual incidence of use of antibacterial drugs for the treatment of mastitis in cattle in Norway and Sweden during the period 1990¢1997 were estimated from drug wholesaler statistics. Although the drugs included in this study are also used in other species and\\/or other indications, mastitis in cattle is by far the most-common indication for their use.
Kari Grave; Christina Greko; Lolita Nilsson; Kristina Odensvik; Tormod M°rk; Marit R°nning
Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens
Objective To evaluate the antibacterial properties of Allium sativum (garlic) cloves and Zingiber officinale (ginger) rhizomes against multi-drug resistant clinical pathogens causing nosocomial infection. Methods The cloves of garlic and rhizomes of ginger were extracted with 95% (v/v) ethanol. The ethanolic extracts were subjected to antibacterial sensitivity test against clinical pathogens. Results Anti-bacterial potentials of the extracts of two crude garlic cloves and ginger rhizomes were tested against five gram negative and two gram positive multi-drug resistant bacteria isolates. All the bacterial isolates were susceptible to crude extracts of both plants extracts. Except Enterobacter sp. and Klebsiella sp., all other isolates were susceptible when subjected to ethanolic extracts of garlic and ginger. The highest inhibition zone was observed with garlic (19.45 mm) against Pseudomonas aeruginosa (P. aeruginosa). The minimal inhibitory concentration was as low as 67.00 Ąg/mL against P. aeruginosa. Conclusions Natural spices of garlic and ginger possess effective anti-bacterial activity against multi-drug clinical pathogens and can be used for prevention of drug resistant microbial diseases and further evaluation is necessary. PMID:23569978
Karuppiah, Ponmurugan; Rajaram, Shyamkumar
Antibacterial activity of natural spices on multiple drug resistant Escherichia coli isolated from drinking water, Bangladesh
Background Spices traditionally have been used as coloring agents, flavoring agents, preservatives, food additives and medicine in Bangladesh. The present work aimed to find out the antimicrobial activity of natural spices on multi-drug resistant Escherichia coli isolates. Methods Anti-bacterial potentials of six crude plant extracts (Allium sativum, Zingiber officinale, Allium cepa, Coriandrum sativum, Piper nigrum and Citrus aurantifolia) were tested against five Escherichia coli isolated from potable water sources at kushtia, Bangladesh. Results All the bacterial isolates were susceptible to undiluted lime-juice. None of them were found to be susceptible against the aqueous extracts of garlic, onion, coriander, pepper and ginger alone. However, all the isolates were susceptible when subjected to 1:1:1 aqueous extract of lime, garlic and ginger. The highest inhibition zone was observed with lime (11 mm). Conclusion Natural spices might have anti-bacterial activity against enteric pathogens and could be used for prevention of diarrheal diseases. Further evaluation is necessary. PMID:21406097
antibacTR: dynamic antibacterial-drug-target ranking integrating comparative genomics, structural analysis and experimental annotation
Background Development of novel antibacterial drugs is both an urgent healthcare necessity and a partially neglected field. The last decades have seen a substantial decrease in the discovery of novel antibiotics, which combined with the recent thrive of multi-drug-resistant pathogens have generated a scenario of general concern. The procedures involved in the discovery and development of novel antibiotics are economically challenging, time consuming and lack any warranty of success. Furthermore, the return-on-investment for an antibacterial drug is usually marginal when compared to other therapeutics, which in part explains the decrease of private investment. Results In this work we present antibacTR, a computational pipeline designed to aid researchers in the selection of potential drug targets, one of the initial steps in antibacterial-drug discovery. The approach was designed and implemented as part of two publicly funded initiatives aimed at discovering novel antibacterial targets, mechanisms and drugs for a priority list of Gram-negative pathogens: Acinetobacter baumannii, Escherichia coli, Helicobacter pylori, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. However, at present this list has been extended to cover a total of 74 fully sequenced Gram-negative pathogens. antibacTR is based on sequence comparisons and queries to multiple databases (e.g. gene essentiality, virulence factors) to rank proteins according to their potential as antibacterial targets. The dynamic ranking of potential drug targets can easily be executed, customized and accessed by the user through a web interface which also integrates computational analyses performed in-house and visualizable on-site. These include three-dimensional modeling of protein structures and prediction of active sites among other functionally relevant ligand-binding sites. Conclusions Given its versatility and ease-of-use at integrating both experimental annotation and computational analyses, antibacTR may effectively assist microbiologists, medicinal-chemists and other researchers working in the field of antibacterial drug-discovery. The public web-interface for antibacTR is available at æhttp://bioinf.uab.cat/antibactrÆ. PMID:24438389
Immobilisation of an antibacterial drug to Ti6Al4V components fabricated using selective laser melting
NASA Astrophysics Data System (ADS)
Bacterial infections from biomedical implants and surgical devices are a major problem in orthopaedic, dental and vascular surgery. Although the sources of contaminations that lead to bacterial infections are known, it is not possible to control or avoid such infections completely. In this study, an approach to immobilise Ciprofloxacin« (an antibacterial drug) to phosphonic acid based self-assembled monolayers (SAMs) adsorbed on a selectively laser melted (SLM) Ti6Al4V structure, has been presented. X-ray photoelectron spectroscopy (XPS) and static water contact angle measurements confirmed the attachment of SAMs and the drug. Results showed that Ciprofloxacin« is highly stable under the oxidative conditions used in this study. In-vitro stability was estimated by immersing the Ciprofloxacin« immobilised substrates in 10 mM of Tris-HCl buffer (pH-7.4) for 42 days. The Tris-HCl buffer was analysed using UV-vis spectrophotometry at 7, 14, 28 and 42 day time intervals to determine the release of the immobilised drug. The drug was observed to release in a sustained manner. 50% of the drug was released after 4 weeks with approximately 40% of the drug remaining after 6 weeks. Antibacterial susceptibility tests revealed that the immobilised drug was therapeutically active upon its release. This study demonstrates the potential to use self-assembled monolayers to modify SLM fabricated surfaces with therapeutics.
Vaithilingam, Jayasheelan; Kilsby, Samuel; Goodridge, Ruth D.; Christie, Steven D. R.; Edmondson, Steve; Hague, Richard J. M.
1. (a) Why are DNA-targeted drugs largely used as anticancer agents and not as, say, antibacterial or antifungal agents?
CHEM 4170 Homework 4 1. (a) Why are DNA-targeted drugs largely used as anticancer agents and not as, say, antibacterial or antifungal agents? (b) Provide an explanation for how anticancer drugs can-damaging drugs mentioned in Question 1). (b) However, some medicinal chemists believe that these compounds
Gates, Kent. S.
History of quinolones and their side effects.
Fluoroquinolone development from 1985 to the present was reviewed. Severe drug adverse events were noted for enoxacin, pefloxacin and fleroxacin, which were phototoxic. Temafloxacin was associated with severe hemolytic-uremic syndrome, lomefloxacin caused phototoxicity and central nervous system (CNS) effects, and sparfloxacin was associated with phototoxicity and QTc prolongation. Tosufloxacin caused severe thrombocytopenia and nephritis, and hepatotoxicity was reported for trovafloxacin. Grepafloxacin was withdrawn due to cardiovascular effects, and clinafloxacin was associated with phototoxicity and hypoglycaemia. The structure of the quinolones directly relates to both their activity and side-effect profiles. The relationship among specific substituents attached to the quinolone nucleus are clarified. The incidence of specific adverse events associated with individual fluoroquinolones was reviewed in a five-year post-marketing surveillance (PMS) study in Japan, in which a total adverse drug reaction (ADR) rate of 1.3% was found for levofloxacin, compared to total ADR rates of 3.3% for pazufloxacin, 3.6% for tosufloxacin, 4.5% for gatifloxacin and 5.4% for balofloxacin. Gastrointestinal effects were the most common adverse events for all fluoroquinolones. Levofloxacin had the lowest rate of CNS effects and skin adverse events among the agents listed. PMID:11549783
Rubinstein, E
Synthesis, antibacterial activity, and biological evaluation of formyl hydroxyamino derivatives as novel potent peptide deformylase inhibitors against drug-resistant bacteria.
Peptide deformylase (PDF) has been identified as a promising target for novel antibacterial agents. In thisĀstudy, a series of novel formyl hydroxyamino derivatives were designed and synthesized as PDF inhibitors and their antibacterial activities were evaluated. Among the potent PDF inhibitors (1o, 1q, 1o', 1q', and 1x), inĀvivo studies showed that compound 1q possesses mild toxicity, a good pharmacokinetic profile and protective effects. The good inĀvivo efficacy and low toxicity suggest that this class of compounds has potential for development and use in future antibacterial drugs. PMID:25151577
Yang, Shouning; Shi, Wei; Xing, Dong; Zhao, Zheng; Lv, Fengping; Yang, Liping; Yang, Yushe; Hu, Wenhao
Laser receptive polyelectrolyte thin films doped with biosynthesized silver nanoparticles for antibacterial coatings and drug delivery applications.
We report a simple method to fabricate multifunctional polyelectrolyte thin films to load and deliver the therapeutic drugs. The multilayer thin films were assembled by the electrostatic adsorption of poly (allylamine hydrochloride) (PAH) and dextran sulfate (DS). The silver nanoparticles (Ag NPs) biosynthesized from novel Hybanthus enneaspermus leaf extract as the reducing agent were successfully incorporated into the film. The biosynthesized Ag NPs showed excellent antimicrobial activity against the range of enteropathogens, which could be significantly enhanced when used with commercial antibiotics. The assembled silver nano composite multilayer films showed rupture and deformation when they are exposed to laser. The Ag NPs act as an energy absorption center, locally heat up the film and rupture it under laser treatment. The antibacterial drug, moxifloxacin hydrochloride (MH) was successfully loaded into the multilayer films. The total amount of MH release observed was about 63% which increased to 85% when subjected to laser light exposure. Thus, the polyelectrolyte thin film reported in our study has significant potential in the field of remote activated drug delivery, antibacterial coatings and wound dressings. PMID:24096301
Sripriya, Jaganathan; Anandhakumar, Sundaramurthy; Achiraman, Shanmugam; Antony, Jacob Joe; Siva, Durairaj; Raichur, Ashok M
Bacterial fatty-acid biosynthesis: a genomics-driven target for antibacterial drug discovery.
In this review we demonstrate how the interplay of genomics, bioinformatics and genomic technologies has enabled an in-depth analysis of the component enzymes of the bacterial fatty-acid biosynthesis pathway as a source of novel antibacterial targets. This evaluation has revealed that many of the enzymes are potentially selective, broad-spectrum antibacterial targets. We also illustrate the suitability of some of these targets for HTS. Furthermore, we discuss how the availability of a robust selectivity assay, mode-of-action assays and numerous crystal structures provide an excellent set of tools with which to initiate integrated programs of research to identify novel antibiotics targeted at these enzymes. PMID:11369293
Payne, D J.; Warren, P V.; Holmes, D J.; Ji, Y; Lonsdale, J T.
Antibacterial activities of Beilschmiedia obscura and six other Cameroonian medicinal plants against multi-drug resistant Gram-negative phenotypes
Background The rapid spread of bacteria expressing multi-drug resistance propels the search for new antibacterial agents. The present study was designed to evaluate the antibacterial activities of the methanol extracts from Beilschmiedia obscura and six other Cameroonian plants against a panel of twenty nine Gram-negative bacteria including Multi-drug resistant (MDR) phenotypes. Methods The phytochemical investigations of the extracts were carried out according to the standard methods and the liquid micro-dilution assay was used for all antibacterial assays. Results Phytochemical analysis showed the presence of alkaloids in all studied extracts. Other chemical classes of secondary metabolites such as anthocyanines, anthraquinones flavonoids, saponins, tannins, sterols and triterpenes were selectively detected in the extracts. The extract from the fruits of Beilschmiedia obscura, Pachypodanthium staudtii leaves and Peperomia fernandopoiana (whole plant) displayed the best spectrum of activity with MIC values ranging from 16 to 1024Ā?g/mL against at least 65% and above of the tested bacteria. The extract from Beilschmiedia obscura was the most active with MIC values below 100Ā?g/mL against ten of the tested bacteria. This extract also showed MBC values below 1024Ā?g/mL against 55.17% of the studied microorganisms. Phenylalanine arginine ?-naphthylamide (PA?N) significantly modulated the activities of extracts from the leaves and fruits of Pachypodanthium staudtii and Beilschmiedia obscura respectively, by increasing their inhibitory activity against Klebsiella pneumoniae KP55 strain at least four fold. Conclusion The overall results of the present investigation provide information for the possible use of the methanol extracts of the studied plant species, especially B. obscura to fight infectious diseases caused by Gram-negative bacteria including MDR phenotypes. PMID:25023038
Discovery of gemifloxacin (Factive, LB20304a): a quinolone of new a generation
Novel quinolone antibacterials, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been designed and synthesized. These fluoroquinolones were found to possess extremely potent antimicrobial activity against Gram-positive organisms including resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA). Among these compounds our development candidate, Gemifloxacin (Factive, LB20304a), showed the
Chang Yong Hong
75 FR 73109 - Guidance for Industry on Antibacterial Drug Products: Use of Noninferiority Trials to Support...
Federal Register 2010, 2011, 2012, 2013, 2014
...information on FDA's current thinking regarding appropriate...NI) clinical trial designs to evaluate antibacterial...products. The Agency's thinking in this area has evolved...indications for the NI trial design. The public comments...the Agency's current thinking on this topic. It...
A Bi-Mix Antibacterial Drug-Delivery System for Regenerative Endodontics. Jadesada Palasuk1
to characterize mechanical, chemical and antibacterial properties. One-way ANOVA (only for fiber diameter strength was not significantly decreased compared to the control except G3. Average fiber diameters were in the nano-scaled range and significantly lower then the control. SEM imaging indicated a submicron fibrous
Zhou, Yaoqi
Clinical Importance and Epidemiology of Quinolone Resistance
The quinolone class of antimicrobial agents is one of most widely used classes of antimicrobial agents in outpatient and inpatient treatment. However, quinolone resistance in gram-positive and gram-negative bacteria has emerged and increased globally. This resistance limits the usefulness of quinolones in clinical practice. The review summarizes mechanisms of quinolone resistance and its epidemiology and implications in the most common clinical settings, urinary tract infections, respiratory tract infections, intraabdominal infections, skin and skin structure infections, and sexually transmitted diseases. PMID:25566402
Kim, Eu Suk
Plasmid-mediated quinolone resistance
Summary Three mechanisms for plasmid-mediated quinolone resistance (PMQR) have been discovered since 1998. Plasmid genes qnrA, qnrB, qnrC, qnrD, qnrS, and qnrVC code for proteins of the pentapeptide repeat family that protects DNA gyrase and topoisomerase IV from quinolone inhibition. The qnr genes appear to have been acquired from chromosomal genes in aquatic bacteria, are usually associated with mobilizing or transposable elements on plasmids, and are often incorporated into sul1-type integrons. The second plasmid-mediated mechanism involves acetylation of quinolones with an appropriate amino nitrogen target by a variant of the common aminoglycoside acetyltransferase AAC(6?)-Ib. The third mechanism is enhanced efflux produced by plasmid genes for pumps QepAB and OqxAB. PMQR has been found in clinical and environmental isolates around the world and appears to be spreading. The plasmid-mediated mechanisms provide only low-level resistance that by itself does not exceed the clinical breakpoint for susceptibility but nonetheless facilitates selection of higher-level resistance and makes infection by pathogens containing PMQR harder to treat. PMID:25584197
Jacoby, George A.; Strahilevitz, Jacob; Hooper, David C.
In Vitro Activity of Ozenoxacin against Quinolone-Susceptible and Quinolone-Resistant Gram-Positive Bacteria
In vitro activity of ozenoxacin, a novel nonfluorinated topical (L. D. Saravolatz and J. Leggett, Clin. Infect. Dis. 37:1210¢1215, 2003) quinolone, was compared with the activities of other quinolones against well-characterized quinolone-susceptible and quinolone-resistant Gram-positive bacteria. Ozenoxacin was 3-fold to 321-fold more active than other quinolones. Ozenoxacin could represent a first-in-class nonfluorinated quinolone for the topical treatment of a broad range of dermatological infections. PMID:24080666
L¾pez, Y.; Tato, M.; Espinal, P.; Garcia-Alonso, F.; Gargallo-Viola, D.; Cant¾n, R.
Role of the water-metal ion bridge in mediating interactions between quinolones and Escherichia coli topoisomerase IV.
Although quinolones have been in clinical use for decades, the mechanism underlying drug activity and resistance has remained elusive. However, recent studies indicate that clinically relevant quinolones interact with Bacillus anthracis (Gram-positive) topoisomerase IV through a critical water-metal ion bridge and that the most common quinolone resistance mutations decrease drug activity by disrupting this bridge. As a first step toward determining whether the water-metal ion bridge is a general mechanism of quinolone-topoisomerase interaction, we characterized drug interactions with wild-type Escherichia coli (Gram-negative) topoisomerase IV and a series of ParC enzymes with mutations (S80L, S80I, S80F, and E84K) in the predicted bridge-anchoring residues. Results strongly suggest that the water-metal ion bridge is essential for quinolone activity against E. coli topoisomerase IV. Although the bridge represents a common and critical mechanism that underlies broad-spectrum quinolone function, it appears to play different roles in B. anthracis and E. coli topoisomerase IV. The water-metal ion bridge is the most important binding contact of clinically relevant quinolones with the Gram-positive enzyme. However, it primarily acts to properly align clinically relevant quinolones with E. coli topoisomerase IV. Finally, even though ciprofloxacin is unable to increase levels of DNA cleavage mediated by several of the Ser80 and Glu84 mutant E. coli enzymes, the drug still retains the ability to inhibit the overall catalytic activity of these topoisomerase IV proteins. Inhibition parallels drug binding, suggesting that the presence of the drug in the active site is sufficient to diminish DNA relaxation rates. PMID:25115926
Aldred, Katie J; Breland, Erin J; Vl?kovß, Vladislava; Strub, Marie-Paule; Neuman, Keir C; Kerns, Robert J; Osheroff, Neil
An interpenetrated bioactive nonlinear optical MOF containing a coordinated quinolone-like drug and Zn(II) for pH-responsive release.
A new interpenetrated bioactive nonlinear optical metal-organic framework [Zn2(ppa)2(1,3-bdc)(H2O)] has been designed and synthesized, which shows both a high drug content of 63.9% and a good slow release effect in simulated physical conditions compared to other non-interpenetrated bioactive MOFs. It also shows a large powder second-harmonic generation (SHG) efficiency of 5.6 times that of KH2PO4 (particle size: 150-200 ?m). PMID:25473930
Duan, Li-Na; Dang, Qin-Qin; Han, Cai-Yun; Zhang, Xian-Ming
In vitro activity of the newer quinolones compared with the classic ones and tobramycin.
The halogenated substitution of quinolone derivatives has given rise to a new group of substances called newer quinolones, which possess extraordinary antibacterial activity in vitro. The aim of our study was to compare the effect of the newer quinolones ciprofloxacin (CIP), norfloxacin (NOR) and enoxacin (ENO) with that of the classical ones nalidixic acid (NA), oxolinic acid (OX) and pipemidic acid (PIP) and with a widely-used aminoglycoside tobramycin (TBR). This was tested on 2,263 strains from clinical isolations. Evaluating the effect of the least active substances as a unit, we generally found the MIC90s to be of the following order: (Formula: see text). The remaining groups among the antibiotics studied are ordered identically, the most potent being the newer quinolones in the following order: CIP is at least four times superior to NOR, which in turn is at least twice as effective as ENO for gram-positive organisms, but only 1.2 times for gram-negative bacilli. PMID:2931382
Boquet Jimķnez, E; Dalet Escribß, F; Caballķ, L
White Paper: Recommendations on the Conduct of Superiority and Organism-Specific Clinical Trials of Antibacterial Agents for the Treatment of Infections Caused by Drug-Resistant Bacterial Pathogens
There is a critical need for new pathways to develop antibacterial agents to treat life-threatening infections caused by highly resistant bacteria. Traditionally, antibacterial agents have been studied in noninferiority clinical trials that focus on one site of infection (eg, pneumonia, intra-abdominal infection). Conduct of superiority trials for infections caused by highly antibiotic-resistant bacteria represents a new, and as yet, untested paradigm for antibacterial drug development. We sought to define feasible trial designs of antibacterial agents that could enable conduct of superiority and organism-specific clinical trials. These recommendations are the results of several years of active dialogue among the white paper's drafters as well as external collaborators and regulatory officials. Our goal is to facilitate conduct of new types of antibacterial clinical trials to enable development and ultimately approval of critically needed new antibacterial agents. PMID:22891041
Improved drug loading and antibacterial activity of minocycline-loaded PLGA nanoparticles prepared by solid/oil/water ion pairing method
Background Low drug entrapment efficiency of hydrophilic drugs into poly(lactic-co-glycolic acid) (PLGA) nanoparticles is a major drawback. The objective of this work was to investigate different methods of producing PLGA nanoparticles containing minocycline, a drug suitable for periodontal infections. Methods Different methods, such as single and double solvent evaporation emulsion, ion pairing, and nanoprecipitation were used to prepare both PLGA and PEGylated PLGA nanoparticles. The resulting nanoparticles were analyzed for their morphology, particle size and size distribution, drug loading and entrapment efficiency, thermal properties, and antibacterial activity. Results The nanoparticles prepared in this study were spherical, with an average particle size of 85¢424 nm. The entrapment efficiency of the nanoparticles prepared using different methods was as follows: solid/oil/water ion pairing (29.9%) > oil/oil (5.5%) > water/oil/water (4.7%) > modified oil/water (4.1%) > nano precipitation (0.8%). Addition of dextran sulfate as an ion pairing agent, acting as an ionic spacer between PEGylated PLGA and minocycline, decreased the water solubility of minocycline, hence increasing the drug entrapment efficiency. Entrapment efficiency was also increased when low molecular weight PLGA and high molecular weight dextran sulfate was used. Drug release studies performed in phosphate buffer at pH 7.4 indicated slow release of minocycline from 3 days to several weeks. On antibacterial analysis, the minimum inhibitory concentration and minimum bactericidal concentration of nanoparticles was at least two times lower than that of the free drug. Conclusion Novel minocycline-PEGylated PLGA nanoparticles prepared by the ion pairing method had the best drug loading and entrapment efficiency compared with other prepared nanoparticles. They also showed higher in vitro antibacterial activity than the free drug. PMID:22275837
Kashi, Tahereh Sadat Jafarzadeh; Eskandarion, Solmaz; Esfandyari-Manesh, Mehdi; Marashi, Seyyed Mahmoud Amin; Samadi, Nasrin; Fatemi, Seyyed Mostafa; Atyabi, Fatemeh; Eshraghi, Saeed; Dinarvand, Rassoul
Hierarchical nested trial design (HNTD) for demonstrating treatment efficacy of new antibacterial drugs in patient populations with emerging bacterial resistance.
In the last decade or so, pharmaceutical drug development activities in the area of new antibacterial drugs for treating serious bacterial diseases have declined, and at the same time, there are worries that the increased prevalence of antibiotic-resistant bacterial infections, especially the increase in drug-resistant Gram-negative infections, limits available treatment options . A recent CDC report, 'Antibiotic Resistance Threats in the United States', indicates that antimicrobial resistance is one of our most serious health threats. However, recently, new ideas have been proposed to change this situation. An idea proposed in this regard is to conduct randomized clinical trials in which some patients, on the basis of a diagnostic test, may show presence of bacterial pathogens that are resistant to the control treatment, whereas remaining patients would show pathogens that are susceptible to the control. The control treatment in such trials can be the standard of care or the best available therapy approved for the disease. Patients in the control arm with resistant pathogens can have the option for rescue therapies if their clinical signs and symptoms worsen. A statistical proposal for such patient populations is to use a hierarchical noninferiority-superiority nested trial design that is informative and allows for treatment-to-control comparisons for the two subpopulations without any statistical penalty. This design can achieve in the same trial dual objectives: (i) to show that the new drug is effective for patients with susceptible pathogens on the basis of a noninferiority test and (ii) to show that it is superior to the control in patients with resistant pathogens. This paper addresses statistical considerations and methods for achieving these two objectives for this design. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID:24957660
Huque, Mohammad F; Valappil, Thamban; Soon, Guoxing Greg
21 CFR 201.24 - Labeling for systemic antibacterial drug products.
Code of Federal Regulations, 2013 CFR
...reduce the development of drug-resistant bacteria and maintain the effectiveness of (insert...or strongly suspected to be caused by bacteria. (b) In the ōIndications and Usage...reduce the development of drug-resistant bacteria and maintain the effectiveness of...
21 CFR 201.24 - Labeling for systemic antibacterial drug products.
Code of Federal Regulations, 2014 CFR
...reduce the development of drug-resistant bacteria and maintain the effectiveness of (insert...or strongly suspected to be caused by bacteria. (b) In the ōIndications and Usage...reduce the development of drug-resistant bacteria and maintain the effectiveness of...
21 CFR 201.24 - Labeling for systemic antibacterial drug products.
Code of Federal Regulations, 2011 CFR
...reduce the development of drug-resistant bacteria and maintain the effectiveness of (insert...or strongly suspected to be caused by bacteria. (b) In the ōIndications and Usage...reduce the development of drug-resistant bacteria and maintain the effectiveness of...
Influence of First-Line Antibiotics on the Antibacterial Activities of Acetone Stem Bark Extract of Acacia mearnsii De Wild. against Drug-Resistant Bacterial Isolates
Background. This study was aimed at evaluating the antibacterial activity of the acetone extract of A. mearnsii and its interactions with antibiotics against some resistant bacterial strains. Methods. The antibacterial susceptibility testing was determined by agar diffusion and macrobroth dilution methods while the checkerboard method was used for the determination of synergy between the antibiotics and the extract. Results. The results showed that the susceptibility of the different bacterial isolates was concentration dependent for the extract and the different antibiotics. With the exception of S. marcescens, the inhibition zones of the extract produced by 20?mg/mL ranged between 18 and 32?mm. While metronidazole did not inhibit any of the bacterial isolates, all the antibiotics and their combinations, except for ciprofloxacin and its combination, did not inhibit Enterococcus faecalis. The antibacterial combinations were more of being antagonistic than of being synergistic in the agar diffusion assay. From the macrobroth dilution, the extract and the antibiotics exerted a varied degree of inhibitory effect on the test organisms. The MIC values of the acetone extract which are in mg/mL are lower than those of the different antibiotics which are in ?g/mL. From the checkerboard assay, the antibacterial combinations showed varied degrees of interactions including synergism, additive, indifference, and antagonism interactions. While antagonistic and additive interactions were 14.44%, indifference interaction was 22.22% and synergistic interaction was 37.78% of the antibacterial combinations against the test isolates. While the additivity/indifference interactions indicated no interactions, the antagonistic interaction may be considered as a negative interaction that could result in toxicity and suboptimal bioactivity. Conclusion. The synergistic effects of the herbal-drug combinations may be harnessed for the discovery and development of more rational evidence-based drug combinations with optimized efficiency in the prevention of multidrug resistance and therapy of multifactorial diseases. PMID:25101132
Olajuyigbe, Olufunmiso O.; Coopoosamy, Roger M.
Influence of First-Line Antibiotics on the Antibacterial Activities of Acetone Stem Bark Extract of Acacia mearnsii De Wild. against Drug-Resistant Bacterial Isolates.
Background. This study was aimed at evaluating the antibacterial activity of the acetone extract of A. mearnsii and its interactions with antibiotics against some resistant bacterial strains. Methods. The antibacterial susceptibility testing was determined by agar diffusion and macrobroth dilution methods while the checkerboard method was used for the determination of synergy between the antibiotics and the extract. Results. The results showed that the susceptibility of the different bacterial isolates was concentration dependent for the extract and the different antibiotics. With the exception of S. marcescens, the inhibition zones of the extract produced by 20?mg/mL ranged between 18 and 32?mm. While metronidazole did not inhibit any of the bacterial isolates, all the antibiotics and their combinations, except for ciprofloxacin and its combination, did not inhibit Enterococcus faecalis. The antibacterial combinations were more of being antagonistic than of being synergistic in the agar diffusion assay. From the macrobroth dilution, the extract and the antibiotics exerted a varied degree of inhibitory effect on the test organisms. The MIC values of the acetone extract which are in mg/mL are lower than those of the different antibiotics which are in ?g/mL. From the checkerboard assay, the antibacterial combinations showed varied degrees of interactions including synergism, additive, indifference, and antagonism interactions. While antagonistic and additive interactions were 14.44%, indifference interaction was 22.22% and synergistic interaction was 37.78% of the antibacterial combinations against the test isolates. While the additivity/indifference interactions indicated no interactions, the antagonistic interaction may be considered as a negative interaction that could result in toxicity and suboptimal bioactivity. Conclusion. The synergistic effects of the herbal-drug combinations may be harnessed for the discovery and development of more rational evidence-based drug combinations with optimized efficiency in the prevention of multidrug resistance and therapy of multifactorial diseases. PMID:25101132
Olajuyigbe, Olufunmiso O; Coopoosamy, Roger M
21 CFR 201.24 - Labeling for systemic antibacterial drug products.
Code of Federal Regulations, 2012 CFR
...unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant...section, under the ōInformation for Patientsö subsection, the labeling must state: Patients should be counseled that...
Controlled drug release characteristics and enhanced antibacterial effect of graphene nanosheets containing gentamicin sulfate
NASA Astrophysics Data System (ADS)
A novel methanol derived graphene (MDG) and gentamicin sulfate nanohybrid was prepared, and the loading and release behaviour of gentamicin on MDG is investigated. An efficient drug loading of 2.57 mg mg-1 was obtained at pH 7. By applying release kinetic models, the mechanism of release of the drug from the MDG matrix was found to be following the Korsmeyer-Peppas model. However, the diffusional release exponent (n) value lies below 0.5 demonstrating that the mechanism controlling the drug release is the Fickian diffusion.A novel methanol derived graphene (MDG) and gentamicin sulfate nanohybrid was prepared, and the loading and release behaviour of gentamicin on MDG is investigated. An efficient drug loading of 2.57 mg mg-1 was obtained at pH 7. By applying release kinetic models, the mechanism of release of the drug from the MDG matrix was found to be following the Korsmeyer-Peppas model. However, the diffusional release exponent (n) value lies below 0.5 demonstrating that the mechanism controlling the drug release is the Fickian diffusion. Electronic supplementary information (ESI) available. See DOI: 10.1039/c1nr10661a
Pandey, Himanshu; Parashar, Vyom; Parashar, Rashmi; Prakash, Rajiv; Ramteke, Promod W.; Pandey, Avinash C.
Distribution of Quinolones, Sulfonamides, Tetracyclines in Aquatic Environment and Antibiotic Resistance in Indochina
Southeast Asia has become the center of rapid industrial development and economic growth. However, this growth has far outpaced investment in public infrastructure, leading to the unregulated release of many pollutants, including wastewater-related contaminants such as antibiotics. Antibiotics are of major concern because they can easily be released into the environment from numerous sources, and can subsequently induce development of antibiotic-resistant bacteria. Recent studies have shown that for some categories of drugs this source-to-environment antibiotic resistance relationship is more complex. This review summarizes current understanding regarding the presence of quinolones, sulfonamides, and tetracyclines in aquatic environments of Indochina and the prevalence of bacteria resistant to them. Several noteworthy findings are discussed: (1) quinolone contamination and the occurrence of quinolone resistance are not correlated; (2) occurrence of the sul sulfonamide resistance gene varies geographically; and (3) microbial diversity might be related to the rate of oxytetracycline resistance. PMID:22363337
Suzuki, Satoru; Hoa, Phan Thi Phuong
[A rapid method of evaluation of the effectiveness of antibacterial drugs].
Efficacy of antibiotics in the treatment of experimental tularemia was studied comparatively on various biological models. It was shown that the antibiotics which proved active against the tularemia microbe in albino mice when studied by the rapid and routine methods were highly efficient in the treatment and prevention of experimental tularemia in rabbits and baboons (hamadryas). The experiments showed basic possibilities to perform rapid estimation (for at least 2 days) of drug efficacy in experimental glanders and melioidosis in golden hamsters. The rapid method developed by the authors was recommended for the use in primary estimation of the efficacy of new drugs in the treatment of tularemia, glanders and melioidosis. PMID:1514871
Oborin, V A; Kravets, I D; Vasil'ev, N T; Vasil'ev, P G; Kornilov, M N
Biosurfactins production by Bacillus amyloliquefaciens R3 and their antibacterial activity against multi-drug resistant pathogenic E. coli.
In this work, the anti-Escherichia coli activity of the bioactive substances produced by Bacillus amyloliquefaciens R3 was examined. A new and cheap medium for production of the anti-E. coli substances which contained 20.0ĀgĀL(-1) soybean powder, 20.0ĀgĀL(-1) wheat flour, pH 6.0 was developed. A crude surfactant concentration of 0.48ĀmgĀmL(-1) was obtained after 27Āh of 10-L fermentation, and the diameter of the clear zone on the plate seeded with the pathogenic E. coli 2# was 23.3Āmm. A preliminary characterization suggested that the anti-E. coli substances produced by B. amyloliquefaciens R3 were the biosurfactins (F1, F2, F3, F4, and F5) with amino acids (GLLVDLL) and hydroxy fatty acids (of 12-15 carbons in length). It was found that all the strains of the pathogenic E. coli showed resistance to several different antibiotics, suggesting that they were the multi-drug resistance and all the strains of the pathogenic E. coli were sensitive to the biosurfactins, indicating that the biosurfactins produced by B. amyloliquefaciens R3 had a broad spectrum of antibacterial activity against the pathogenic E. coli with multi-drug resistant profiles. After the treatment with the purified biosurfactin (F1), the cell membrane of both the whole cells and protoplasts of the E. coli 2# was damaged and the whole cells of the bacterium were broken. PMID:25407729
Chi, Zhe; Rong, Yan-Jun; Li, Yang; Tang, Mei-Juan; Chi, Zhen-Ming
Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump.
Drug efflux pumps confer resistance upon bacteria to a wide range of antibiotics from various classes. The expression of efflux pumps are also implicated in virulence and biofilm formation. Moreover, organisms can only acquire resistance in the presence of active drug efflux pumps. Therefore, efflux pump inhibitors (EPIs) are attractive compounds to reverse multidrug resistance and to prevent the development of resistance in clinically relevant bacterial pathogens. We investigated the potential of pure compounds isolated from plants to act as EPIs. In silico screening was used to predict the bioactivity of plant compounds and to compare that with the known EPI, phe-arg-?-naphthylamide (PA?N). Subsequently, promising products have been tested for their ability to inhibit efflux. Plumbagin nordihydroguaretic acid (NDGA) and to a lesser degree shikonin, acted as sensitizers of drug-resistant bacteria to currently used antibiotics and were able to inhibit the efflux pump-mediated removal of substrate from cells. We demonstrated the feasibility of in silico screening to identify compounds that potentiate the action of antibiotics against drug-resistant strains and which might be potentially useful lead compounds for an EPI discovery program. PMID:25224951
Ohene-Agyei, Thelma; Mowla, Rumana; Rahman, Taufiq; Venter, Henrietta
Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump
Drug efflux pumps confer resistance upon bacteria to a wide range of antibiotics from various classes. The expression of efflux pumps are also implicated in virulence and biofilm formation. Moreover, organisms can only acquire resistance in the presence of active drug efflux pumps. Therefore, efflux pump inhibitors (EPIs) are attractive compounds to reverse multidrug resistance and to prevent the development of resistance in clinically relevant bacterial pathogens. We investigated the potential of pure compounds isolated from plants to act as EPIs. In silico screening was used to predict the bioactivity of plant compounds and to compare that with the known EPI, phe-arg-?-naphthylamide (PA?N). Subsequently, promising products have been tested for their ability to inhibit efflux. Plumbagin nordihydroguaretic acid (NDGA) and to a lesser degree shikonin, acted as sensitizers of drug-resistant bacteria to currently used antibiotics and were able to inhibit the efflux pump-mediated removal of substrate from cells. We demonstrated the feasibility of in silico screening to identify compounds that potentiate the action of antibiotics against drug-resistant strains and which might be potentially useful lead compounds for an EPI discovery program. PMID:25224951
Ohene-Agyei, Thelma; Mowla, Rumana; Rahman, Taufiq; Venter, Henrietta
Comparative activity of the topical quinolone OPC7251 against bacteria associated with acne vulgaris
The antibacterial activity of the topical quinolone OPC-7251 against bacteria commonly found in acne vulgaris was tested in vitro by an agar dilution method. The MIC50 was 0.25 mg\\/l forPropionibacterium acnes, 0.125 mg\\/l forPropionibacterium granulosum, 0.03 mg\\/l forStaphylococcus aureus and 0.06 mg\\/l for coagulase-negative staphylococci. Compared with seven other antibiotics tested (ciprofloxacin, penicillin, erythromycin, tetracycline, clindamycin, fusidic acid and gentamicin),
K. Vogtl; J. Hermann; U. Blume; H. Gollnick; H. Hahn; U. F. Haustein; C. E. Orfanos
SHORT REPORT Open Access Emergence of quinolone resistance among
Misatou and Didier Monchy Abstract Background: Cross-resistance to quinolones and beta-lactams is frequent Background Quinolones and beta-lactams are widely used antibiotics for the treatment of bacterial infections bacteria that are not only quinolone-resistant but also beta-lactam-resis- tant and vice versa
Boyer, Edmond
Quinolones and multidrug-resistant tuberculosis.
The prevalence of initial resistance of multidrug-resistant tuberculosis (MDR-TB) to at least isoniazid (INH) and rifampicin (RFP) in Thailand during the period 1993-1997 is reported; in this era, trends for INH + RFP + streptomycin (SM) and ethambutol (EMB), INH + RFP + SM or EMB and MDR-TB were stable. The prevalence of acquired MDR-TB is on a slight downward trend, with the latest level at 22.6%. Recommended management of MDR-TB is outlined and advantages and disadvantages of these guidelines discussed. The role of ofloxacin in MDR-TB is presented, with results from a study performed by the Thailand CDC showing that the percentage of strains resistant to ofloxacin was 4.3%, and to ciprofloxacin was 8.3%. The resistance to both ofloxacin and ciprofloxacin was very low at 1.4%. The percentage of cross-resistance between these fluoroquinolones was also low; 33% resistant to ofloxacin were also resistant to ciprofloxacin and only 17% of those resistant to ciprofloxacin were also resistant to ofloxacin. Results from a clinical trial evaluating ofloxacin with other drugs for MDR-TB are also reported. The regimen comprised ofloxacin 600 mg/day, pyrazinamide (PZA), two to three months of kanamycin (KM) or amikacin (AMK), para-aminosalicylic acid (PAS) plus EMB or thiacetazone. Drugs were given for 18 months. Follow-up was every three months for two years. Preliminary results revealed that the percentage of acquired MDR-TB resistant to specific agents was as follows: 36% resistant to INH and RFP, 23% resistant to INH, RFP plus EMB, 27% resistant to INH, RFP and SM, and 14% resistant to all four of these agents (INH + RFP + SM + EMB). All isolates were sensitive to ofloxacin. At one month of treatment, sputum culture conversion was approximately 25%, climbing to 93% by nine months of treatment. Treatment with ofloxacin in a combined regimen achieved a success rate of 78%. The role of quinolones in preventing TB in MDR-TB contacts is also discussed. PMID:10449893
Maranetra, K N
[Comparison of MICs of new quinolones obtained using agar-dilution and broth-microdilution procedures].
Minimum inhibitory concentrations (MIC) of new quinolones against both Gram-positive and Gram-negative bacteria obtained using agar-dilution and broth-microdilution procedures were compared. A primary regression curve and a correlation coefficient (r) between 2 MICs for each of ofloxacin, ciprofloxacin, tosufloxacin, sparfloxacin or balofloxacin were calculated. For the 5 quinolones, average correlation coefficients were 0.891 for the Gram-positive bacteria tested, and 0.865 for the Gram-negative bacteria. The range of, correlation coefficients for the Gram-positive bacteria for these drugs was from 0.835 to 0.919, and that for the Gram-negative bacteria was from 0.815 to 0.865. From these data, it is clear that there is a good correlation between the 2 MICs of the new quinolones obtained using the agar-dilution and the broth-microdilution procedures. It was also shown that the value of the slope of the regression curves were nearly the same for the 5 quinolones tested. However, some particular strains of Morganella morganii, Pseudomonas cepacia, Xanthomonas maltophilia, Pseudomonas aeruginosa and Streptococcus pneumoniae exhibited different correlation coefficients from other strains. PMID:7752452
Iwasaki, H; Tsuji, A; Kaneko, Y; Goto, S
Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding.
DNA gyrase and topoisomerase IV control bacterial DNA topology by breaking DNA, passing duplex DNA through the break, and then resealing the break. This process is subject to reversible corruption by fluoroquinolones, antibacterials that form drug-enzyme-DNA complexes in which the DNA is broken. The complexes, called cleaved complexes because of the presence of DNA breaks, have been crystallized and found to have the fluoroquinolone C-7 ring system facing the GyrB/ParE subunits. As expected from x-ray crystallography, a thiol-reactive, C-7-modified chloroacetyl derivative of ciprofloxacin (Cip-AcCl) formed cross-linked cleaved complexes with mutant GyrB-Cys(466) gyrase as evidenced by resistance to reversal by both EDTA and thermal treatments. Surprisingly, cross-linking was also readily seen with complexes formed by mutant GyrA-G81C gyrase, thereby revealing a novel drug-gyrase interaction not observed in crystal structures. The cross-link between fluoroquinolone and GyrA-G81C gyrase correlated with exceptional bacteriostatic activity for Cip-AcCl with a quinolone-resistant GyrA-G81C variant of Escherichia coli and its Mycobacterium smegmatis equivalent (GyrA-G89C). Cip-AcCl-mediated, irreversible inhibition of DNA replication provided further evidence for a GyrA-drug cross-link. Collectively these data establish the existence of interactions between the fluoroquinolone C-7 ring and both GyrA and GyrB. Because the GyrA-Gly(81) and GyrB-Glu(466) residues are far apart (17 ?) in the crystal structure of cleaved complexes, two modes of quinolone binding must exist. The presence of two binding modes raises the possibility that multiple quinolone-enzyme-DNA complexes can form, a discovery that opens new avenues for exploring and exploiting relationships between drug structure and activity with type II DNA topoisomerases. PMID:24497635
Mustaev, Arkady; Malik, Muhammad; Zhao, Xilin; Kurepina, Natalia; Luan, Gan; Oppegard, Lisa M; Hiasa, Hiroshi; Marks, Kevin R; Kerns, Robert J; Berger, James M; Drlica, Karl
Synthesis and Structure-Activity Relationships of Antimalarial 4-oxo-3-carboxyl quinolones
Malaria is endemic in tropical and subtropical regions of Africa, Asia, and the Americas. The increasing prevalence of multi-drug-resistant Plasmodium falciparum drives the ongoing need for the development of new antimalarial drugs. In this light, novel scaffolds to which the parasite has not been exposed are of particular interest. Recently, workers at the Swiss Tropical Institute discovered two novel 4-oxo-3-carboxyl quinolones active against the intra-erythrocytic stages of P. falciparum while carrying out rationally directed low-throughput screening of potential antimalarial agents as part of an effort directed by the World Health Organization. Here we report the design, synthesis, and preliminary pharmacologic characterization of a series of analogues of 4-oxo-3-carboxyl quinolones. These studies indicate that the series has good potential for preclinical development. PMID:20206533
Zhang, Yiqun; Guiguemde, W. Armand; Sigal, Martina; Zhu, Fangyi; Connelly, Michele C.; Nwaka, Solomon
Cytotoxic, antibacterial, DNA interaction and superoxide dismutase like activities of sparfloxacin drug based copper(II) complexes with nitrogen donor ligands
NASA Astrophysics Data System (ADS)
The novel neutral mononuclear copper(II) complexes with fluoroquinolone antibacterial drug, sparfloxacin and nitrogen donor heterocyclic ligand have been synthesized and characterized. An antimicrobial efficiency of the complexes has been tested against five different microorganisms and showed diverse biological activity. The interaction of complex with Herring sperm (HS) DNA was investigated using viscosity titration and absorption titration techniques. The results indicate that the complexes bind to DNA by intercalative mode and have rather high DNA-binding constants. DNA cleavage study showed better cleaving ability of the complexes compare to metal salt and standard drug. All the complexes showed good cytotoxic activity with LC50 values ranging from 4.89 to 11.94 ?g mL-1. Complexes also exhibit SOD-like activity with their IC50 values ranging from 0.717 to 1.848 ?M.
Patel, Mohan N.; Joshi, Hardik N.; Patel, Chintan R.
Optimization of endochin-like quinolones for antimalarial activity
Structural analogs of the antimalarial Endochin were synthesized and screened for antiplasmodial activity against drug sensitive and multidrug resistant strains of Plasmodium falciparum. Structural features have been identified that are associated with improved potency while other features are associated with equipotency against an atovaquone-resistant clinical isolate. Relative to endochin the most active compound ELQ-121 shows ? 100-fold improvement in IC50 for inhibition of P. falciparum in vitro and it also exhibits enhanced metabolic stability. A polyethylene glycol carbonate ester prodrug of ELQ-121 demonstrated in vivo efficacy against P. yoelii in mice. This is the first report of an endochin-like quinolone that is efficacious in treating malaria in a mammalian host. PMID:21040724
Winter, Rolf; Kelly, Jane X.; Smilkstein, Martin J.; Hinrichs, David; Koop, Dennis R.; Riscoe, Michael K.
Quinolone and macrolide resistance in Campylobacter jejuni and C. coli: resistance mechanisms and trends in human isolates.
The incidence of human Campylobacter jejuni and C. coli infections has increased markedly in many parts of the world in the last decade as has the number of quinolone-resistant and, to a lesser extent, macrolide-resistant Campylobacter strains causing infections. We review macrolide and quinolone resistance in Campylobacter and track resistance trends in human clinical isolates in relation to use of these agents in food animals. Susceptibility data suggest that erythromycin and other macrolides should remain the drugs of choice in most regions, with systematic surveillance and control measures maintained, but fluoroquinolones may now be of limited use in the empiric treatment of Campylobacter infections in many regions. PMID:11266291
Engberg, J.; Aarestrup, F. M.; Taylor, D. E.; Gerner-Smidt, P.; Nachamkin, I.
NSDL National Science Digital Library
Today, it's hard to find dishwashing liquids or hand soaps that don't advertise their "antibacterial" chemicals. But while it's unclear whether these chemicals actually help us, there's new reason to believe they might do more harm than good. This Science Update examines the common antibacterial agent, Triclocarban or TCC, which is found in hand soaps and other household products.
Science Update
Cytotoxic and antibacterial substances against multi-drug resistant pathogens from marine sponge symbiont: Citrinin, a secondary metabolite of Penicillium sp.
Objective To Isolate, purify, characterize, and evaluate the bioactive compounds from the sponge-derived fungus Penicillium sp. FF001 and to elucidate its structure. Methods The fungal strain FF001 with an interesting bioactivity profile was isolated from a marine Fijian sponge Melophlus sp. Based on conidiophores aggregation, conidia development and mycelia morphological characteristics, the isolate FF001 was classically identified as a Penicillium sp. The bioactive compound was identified using various spectral analysis of UV, high resolution electrospray ionization mass spectra, 1H and 13C NMR spectral data. Further minimum inhibitory concentrations (MICs) assay and brine shrimp cytotoxicity assay were also carried out to evaluate the biological properties of the purified compound. Results Bioassay guided fractionation of the EtOAc extract of a static culture of this Penicillium sp. by different chromatographic methods led the isolation of an antibacterial, anticryptococcal and cytotoxic active compound, which was identified as citrinin (1). Further, citrinin (1) is reported for its potent antibacterial activity against methicillin-resistant Staphylococcus aureus (S. aureus), rifampicin-resistant S. aureus, wild type S. aureus and vancomycin-resistant Enterococcus faecium showed MICs of 3.90, 0.97, 1.95 and 7.81 Ąg/mL, respectively. Further citrinin (1) displayed significant activity against the pathogenic yeast Cryptococcus neoformans (MIC 3.90 Ąg/mL), and exhibited cytotoxicity against brine shrimp larvae LD50 of 96 Ąg/mL. Conclusions Citrinin (1) is reported from sponge associated Penicillium sp. from this study and for its strong antibacterial activity against multi-drug resistant human pathogens including cytotoxicity against brine shrimp larvae, which indicated that sponge associated Penicillium spp. are promising sources of natural bioactive metabolites. PMID:23620853
Subramani, Ramesh; Kumar, Rohitesh; Prasad, Pritesh; Aalbersberg, William
Evaluation of a topical herbal drug for its in-vivo immunomodulatory effect on cytokines production and antibacterial activity in bovine subclinical mastitis
Background: Antibiotics have been in use in the treatment of bovine mastitis since decades; however, their use is associated with cost issues and human health concern. Use of herbal drugs does not generally carry these disadvantages. Many plants/herbs have been evaluated in the treatment of bovine mastitis with additional property of immunomodulation in affected mammary gland. Aim: To evaluate a topical herbal drug in two breeds of cattle for its in-vivo immunomodulatory effect on cytokines production and antibacterial activity in bovine subclinical mastitis. Materials and Methods: The response to treatment was evaluated by enumerating somatic cell count (SCC), determining total bacterial load, and studying the expression of different cytokines (interleukin [IL]-6, IL-8, IL-12, granulocyte macrophage-colony stimulating factor, interferon (IFN)-? and tumor necrosis factor [TNF]-?). Results: The pre- and post-treatment SCC in mastitic quarters statistically did not differ significantly, however, total bacterial load declined significantly from day 0 onwards in both the breeds. Highly significant differences (P < 0.01) were observed in all the cytokines on day 0, 5, and 21 postlast treatment in both the breeds. The expression level of all the cytokines showed a significant increase on day 5, while a decrease was noticed on day 21 in both the breeds of cattle. The comparison of cytokine expression profiles between crossbred and Gir cattle revealed a significant difference in expression of IL-6 and TNF-?. However, other cytokines exhibited a similar pattern of expression in both breeds, which was non-significant. Conclusion: The topical herbal drug exhibited antibacterial and immunomodulatory activities in subclinical mastitis and thus the work supports its use as alternative herbal therapy against subclinical udder infection in bovines. PMID:25558168
Bhatt, Vaibhav D.; Shah, Tejas M.; Nauriyal, Dev S.; Kunjadia, Anju P.; Joshi, Chaitanya G.
There should be no ESKAPE for febrile neutropenic cancer patients: the dearth of effective antibacterial drugs threatens anticancer efficacy.
The success of modern anticancer treatment is a composite function of enhanced efficacy of surgical, radiation and systemic treatment strategies and of our collective clinical abilities in supporting patients through the perils of their cancer journeys. Despite the widespread availability of antibacterial therapies, the threat of community- or healthcare facility-acquired bacterial infection remains a constant risk to patients during this journey. The rising prevalence of colonization by multidrug-resistant (MDR) bacteria in the population, acquired through exposure from endemic environments, antimicrobial stewardship and infection prevention and control strategies notwithstanding, increases the likelihood that such organisms may be the cause of cancer treatment-related infection and the likelihood of antibacterial treatment failure. The high mortality associated with invasive MDR bacterial infection increases the likelihood that many patients may not survive long enough to reap the benefits of enhanced anticancer treatments, thus threatening the societal investment in the cancer journey. Since cancer care providers arguably no longer have, and are unlikely to have in the foreseeable future, the antibacterial tools to reliably rescue patients from harm's way, the difficult ethical debate over the risks and benefits of anticancer treatments must now be reopened. PMID:23299574
Bow, E J
In vitro and in vivo antibacterial activities of Q-35, a novel fluoroquinolone.
Q-35, a new fluoroquinolone, was evaluated for its in vitro and in vivo antibacterial activities. In vitro antibacterial activity against gram-positive bacteria was almost equal to that of sparfloxacin or tosufloxacin, but its activity against gram-negative bacteria was 2 times or more lower than that of other quinolones tested. In experimental septicemia, the in vivo activity of Q-35 reflected its in vitro antibacterial activity. In respiratory tract infections with Streptococcus pneumoniae TMS-3 in mice, Q-35 showed a therapeutic effect similar to sparfloxacin and tosufloxacin. Q-35 showed almost the same activity as that of ofloxacin in mice with pyelonephritic infection due to Escherichia coli TMS-3. The peak levels of Q-35 in murine serum, lungs and kidneys after a single oral administration were intermediate compared to those of tested quinolones. PMID:7758353
Iwasaki, H; Miyazaki, S; Tsuji, A; Yamaguchi, K; Goto, S
Quinolones Sensitize Gram-Negative Bacteria to Antimicrobial Peptides
The treatment of infections caused by bacteria resistant to the vast majority of antibiotics is a challenge worldwide. Antimicrobial peptides (APs) make up the front line of defense in those areas exposed to microorganisms, and there is intensive research to explore their use as new antibacterial agents. On the other hand, it is known that subinhibitory concentrations of antibiotics affect the expression of numerous bacterial traits. In this work we evaluated whether treatment of bacteria with subinhibitory concentrations of quinolones may alter the sensitivity to APs. A 1-h treatment of Klebsiella pneumoniae with 0.25ū the MIC of ciprofloxacin rendered bacteria more sensitive to polymyxins B and E, human neutrophil defensin 1, and ?-defensin 1. Levofloxacin and nalidixic acid at 0.25ū the MICs also increased the sensitivity of K. pneumoniae to polymyxin B, whereas gentamicin and ceftazidime at 0.25ū the MICs did not have such an effect. Ciprofloxacin also increased the sensitivities of K. pneumoniae ciprofloxacin-resistant strains to polymyxin B. Two other pathogens, Pseudomonas aeruginosa and Haemophilus influenzae, also became more sensitive to polymyxins B and E after treatment with 0.25ū the MIC of ciprofloxacin. Incubation with ciprofloxacin did not alter the expression of the K. pneumoniae loci involved in resistance to APs. A 1-N-phenyl-naphthylamine assay showed that ciprofloxacin and levofloxacin increased the permeabilities of the K. pneumoniae and P. aeruginosa outer membranes, while divalent cations antagonized this action. Finally, we demonstrated that ciprofloxacin and levofloxacin increased the binding of APs to the outer membrane by using dansylated polymyxin B. PMID:16801413
Campos, Miguel A.; Morey, Pau; Bengoechea, Josķ A.
4-Quinolone Alkaloids from Melochia odorata
The methanol extract of Melochia odorata yielded three 4-quinolone alkaloids including waltherione A (1) and two new alkaloids, waltherione C (2) and waltherione D (3). Waltheriones A and C showed significant activities in an in vitro anti-HIV cytoprotection assay at concentrations of 56.2 and 0.84 ?M, and inhibition of HIV P24 formation of more than 50% at 1.7 and 0.95 ?M, respectively. The structures of the alkaloids were established by spectroscopic data interpretation. PMID:24392742
Jadulco, Raquel C.; Pond, Christopher D.; Van Wagoner, Ryan M.; Koch, Michael; Gideon, Osia G.; Matainaho, Teatulohi K.; Piskaut, Pius; Barrows, Louis R.
The ocean contains a host of macroscopic life in a great microbial soup. Unlike the terrestrial environment, an aqueous environment provides perpetual propinquity and blurs spatial distinctions. Marine organisms are under a persistent threat of infection by resident pathogenic microbes including bacteria, and in response they have engineered complex organic compounds with antibacterial activity from a diverse set of biological precursors. The diluting effect of the ocean drives the construction of potent molecules that are stable to harsh salty conditions. Members of each class of metaboliteŚribosomal and non-ribosomal peptides, alkaloids, polyketides, and terpenesŚhave been shown to exhibit antibacterial activity. The sophistication and diversity of these metabolites points to the ingenuity and flexibility of biosynthetic processes in Nature. Compared with their terrestrial counterparts, antibacterial marine natural products have received much less attention. Thus, a concerted effort to discover new antibacterials from marine sources has the potential to contribute significantly to the treatment of the ever increasing drug-resistant infectious diseases. PMID:20845412
Hughes, Chambers C.; Fenical, William
Changes of the Quinolones Resistance to Gram-positive Cocci Isolated during the Past 8 Years in the First Bethune Hospital
NASA Astrophysics Data System (ADS)
This study was to investigate the quinolones resistance to gram-positive cocci isolated in the First Bethune Hospital during the past 8 years. Disk diffusion test was used to study the antimicrobial resistance. The data were analyzed by WHONET 5 software according to Clinical and Laboratory Standards Institute (CLSI). The rates of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative Staphylococci (MRCNS) were 50.8%?83.3% and 79.4%?81.5%during the past 8 years, respectively. In recent 8 years, the quinolones resistance to gram-positive cocci had increased. Monitoring of the quinolones resistance to gram-positive cocci should be strengthened. The change of the antimicrobial resistance should be investigated in order to guide rational drug usage in the clinic and prevent bacterial strain of drug resistance from being transmitted.
Xu, Jiancheng; Chen, Qihui; Yao, Hanxin; Zhou, Qi
Palladium(II) complexes as biologically potent metallo-drugs: Synthesis, spectral characterization, DNA interaction studies and antibacterial activity
NASA Astrophysics Data System (ADS)
Four novel mononuclear Pd(II) complexes have been synthesized with the biologically active Schiff base ligands (L1-L4) derived from 3-amino-2-methyl-4(3H)-quinazolinone. The structure of the complexes has been proposed by elemental analysis, molar conductance, IR, 1H NMR, mass, UV-Vis spectrometric and thermal studies. The investigation of interaction of the complexes with calf thymus DNA (CT-DNA) has been performed with absorption and fluorescence spectroscopic studies. The nuclease activity was done using pUC19 supercoiled DNA by gel-electrophoresis. All the ligands and their Pd(II) complexes have also been screened for their antibacterial activity by discolor diffusion technique.
Prasad, Kollur Shiva; Kumar, Linganna Shiva; Chandan, Shivamallu; Naveen Kumar, R. M.; Revanasiddappa, Hosakere D.
Anti-inflammatory drugs interacting with Zn (II) metal ion based on thiocyanate and azide ligands: Synthesis, spectroscopic studies, DFT calculations and antibacterial assays
NASA Astrophysics Data System (ADS)
Zinc (II) complexes with non-steroidal anti-inflammatory drugs (NSAIDs) naproxen (nap) and ibuprofen (ibu) were synthesized in the presence of nitrogen donor ligands (thiocyanate or azide). The complexes were characterized by elemental analysis, FT-IR, 1H NMR and UV-Vis spectroscopes. The binding modes of the ligands in complexes were established by means of molecular modeling of the complexes, and calculation of their IR, NMR and absorption spectra at DFT (TDDFT)/B3LYP level were studied. The experimental and calculated data verified monodentate binding through the carboxylic oxygen atoms of anti-inflammatory drugs in the zinc complexes. The calculated 1H, FT-IR and UV-Vis data are in better agreement with the experimental results, and confirm the predicted tetrahedral structures for the Zn (II) complexes. In addition to DFT calculations of complexes, natural bond orbital (NBO) was performed at B3LYP/6-31+G(d,p) level of theory. Biological studies showed the antibacterial activity of zinc complexes against Gram-positive and Gram-negative bacterial strains.
Chiniforoshan, Hossein; Tabrizi, Leila; Hadizade, Morteza; Sabzalian, Mohammad R.; Chermahini, Alireza Najafi; Rezapour, Mehdi
Development of an optical surface plasmon resonance biosensor assay for (fluoro)quinolones in egg, fish, and poultry meat.
The aim of this study was to develop an optical biosensor inhibition immunoassay, based on the surface plasmon resonance (SPR) principle, for use as a screening test for 13 (fluoro)quinolones, including flumequine, used as veterinary drugs in food-producing animals. For this, we immobilised various quinolone derivatives on the sensor chip and tested binding of a range of different antibodies (polyclonal and one engineered antibody) in the presence and absence of free (fluoro)quinolones. The main challenge was to detect flumequine in an assay giving good results for the other compounds. One antigen-antibody combination proved satisfactory: polyclonal antibodies raised against a dual immunogen and, on the sensor chip, a fluoroquinolone derivative. It was the first time that this concept of the bi-active antibody was described in the literature. The assay, optimised for detection in three matrices (poultry muscle, fish, and egg), was tested on incurred samples prepared by liquid extraction followed by two washing steps. This rapid, simple method proved adequate for detecting at least 13 (fluoro)quinolones at concentrations below established maximum residue levels (MRLs). The reference molecule norfloxacin could be detected in the range of 0.1-10 microg kg(-1) in extracts of egg and poultry meat and in the range of 0.1-100 microg kg(-1) in extracts of fish. The determined midpoints of these calibration curves were about 1, 1.5 and 3 microg kg(-1) in poultry meat, egg and fish, respectively. PMID:18620924
Huet, A-C; Charlier, C; Singh, G; Godefroy, S Benrejeb; Leivo, J; Vehniõinen, M; Nielen, M W F; Weigel, S; Delahaut, Ph
Challenges of Antibacterial Discovery
Summary: The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort. PMID:21233508
Silver, Lynn L.
Quinolone resistance mediated by norA: physiologic characterization and relationship to flqB, a quinolone resistance locus on the Staphylococcus aureus chromosome.
We identified a quinolone resistance locus, flqB, linked to transposon insertion omega 1108 and fus on the SmaI D fragment of the Staphylococcus aureus NCTC 8325 chromosome, the same fragment that contains the norA gene. S. aureus norA cloned from flqB and flqB+ strains in Escherichia coli differed only in a single nucleotide in the putative promoter region. There was no detectable change in the number of copies of norA on the chromosomes of flqB strains, but they had increased levels of norA transcripts. Cloned norA produced resistance to norfloxacin and other hydrophilic quinolones and reduced norfloxacin accumulation in intact cells that was energy dependent, suggesting active drug efflux as the mechanism of resistance. Drug efflux was studied by measurement of norfloxacin uptake into everted inner membrane vesicles prepared from norA-containing E. coli cells. Vesicles exhibited norfloxacin uptake after the addition of lactate or NADH, and this uptake was abolished by carbonyl cyanide m-chlorophenylhydrazone and nigericin but not valinomycin, indicating that it was linked to the pH gradient across the cell membrane. Norfloxacin uptake into vesicles was also saturable, with an apparent Km of 6 microM, a concentration between those that inhibit the growth of flqB and flqB+ S. aureus cells, indicating that drug uptake is mediated by a carrier with a high apparent affinity for norfloxacin. Ciprofloxacin and ofloxacin competitively inhibited norfloxacin uptake into vesicles. Reserpine, which inhibits the multidrug efflux mediated by the bmr gene of bacillus subtilis, which is similar to norA, abolished norfloxacin uptake into vesicles as well as the norfloxacin resistance of an flqB mutant, suggesting a potential means for circumventing quinolone resistance as a result of drug efflux in S. aureus. These findings indicate that the chromosomal flqB resistance locus is associated with increased levels of expression of norA and strongly suggest that the NorA protein itself functions as a drug transporter that is coupled to the proton gradient across the cell membrane. PMID:8092836
Ng, E Y; Trucksis, M; Hooper, D C
Mode of action of the new quinolones: New data
New details of the molecular interactions of quinolones with their target DNA gyrase and DNA have come from the nucleotide sequences of thegyrA genes from resistant mutants ofEscherichia coli and wild-type strains of other bacteria and studies of gyrase A tryptic fragments, all suggesting the importance of an amino-terminal domain in quinolone action. Alterations in DNA supertwisting were also associated
D. C. Hooper; J. S. Wolfson
Quinolones with Enhanced Bactericidal Activity Induce Autolysis in Streptococcus pneumoniae
Objectives: DC-159a and sitafloxacin show greater bactericidal activity against Streptococcus pneumoniae than garenoxacin and other quinolones. We investigated whether the autolysis induced by these quinolones contributes to their rapid bactericidal activity. Methods: Time-kill studies were conducted against a S. pneumoniae clinical isolate in broth with choline chloride, which is known to inhibit autolytic amidases, and lytA mutants. Western blot analysis
Ryo Okumura; Kazuki Hoshino; Tsuyoshi Otani; Tomoko Yamamoto
Bactericidal activity of gemifloxacin and other quinolones against Streptococcus pneumoniae.
This study compared the bactericidal activity of gemifloxacin (SB-265805) and a panel of test quinolones against two ciprofloxacin-resistant pneumococcal strains (Streptococcus pneumoniae 502226 and 503244) and one ciprofloxacin-sensitive strain (S. pneumoniae C3LN4). Activities were compared by calculating the bactericidal index of these agents. Gemifloxacin was found to be the most bactericidal quinolone tested against these strains. This finding confirms previous data indicating the superior in vitro activity of gemifloxacin against pneumococci, including ciprofloxacin-resistant strains. Although both ciprofloxacin-resistant strains tested had similar quinolone MICs, they differed considerably in their susceptibility to the bactericidal action of these agents. S. pneumoniae 502226 was more readily killed by quinolones than S. pneumoniae 503244 but, as would be expected, both were less susceptible than the ciprofloxacin-sensitive strain. Of the quinolones tested, trovafloxacin showed disproportionally poor activity against the ciprofloxacin-resistant strains even though potent activity was present against the ciprofloxacin-sensitive strain. These data highlight the importance of assessing quinolone bactericidal activity in addition to the MIC when evaluating new members of this antimicrobial class. PMID:10824041
Morrissey, I; George, J T
Differences in susceptibility to quinolones of outer membrane mutants of Salmonella typhimurium and Escherichia coli.
The mechanism of penetration of quinolones through the bacterial outer membrane was studied with lipopolysaccharide-deficient and porin-deficient mutants. The data indicated that the lipopolysaccharide layer might form a permeability barrier for hydrophobic quinolones such as nalidixic acid but not for hydrophilic quinolones such as norfloxacin and ciprofloxacin. The results also showed that quinolones with a low relative hydrophobicity appeared to permeate through OmpF porin, whereas quinolones with a low relative hydrophobicity appeared to permeate through OmpF porin, whereas quinolones with a high relative hydrophobicity appeared to permeate through both OmpF porin and phospholipid bilayers. PMID:3521490
Hirai, K; Aoyama, H; Irikura, T; Iyobe, S; Mitsuhashi, S
Antibacterial Activity of Novel Cationic Peptides against Clinical Isolates of Multi-Drug Resistant Staphylococcus pseudintermedius from Infected Dogs
Staphylococcus pseudintermedius is a major cause of skin and soft tissue infections in companion animals and has zoonotic potential. Additionally, methicillin-resistant S. pseudintermedius (MRSP) has emerged with resistance to virtually all classes of antimicrobials. Thus, novel treatment options with new modes of action are required. Here, we investigated the antimicrobial activity of six synthetic short peptides against clinical isolates of methicillin-susceptible and MRSP isolated from infected dogs. All six peptides demonstrated potent anti-staphylococcal activity regardless of existing resistance phenotype. The most effective peptides were RRIKA (with modified C terminus to increase amphipathicity and hydrophobicity) and WR-12 (?-helical peptide consisting exclusively of arginine and tryptophan) with minimum inhibitory concentration50 (MIC50) of 1 ĄM and MIC90 of 2 ĄM. RR (short anti-inflammatory peptide) and IK8 ōD isoformö demonstrated good antimicrobial activity with MIC50 of 4 ĄM and MIC90 of 8 ĄM. Penetratin and (KFF)3K (two cell penetrating peptides) were the least effective with MIC50 of 8 ĄM and MIC90 of 16 ĄM. Killing kinetics revealed a major advantage of peptides over conventional antibiotics, demonstrating potent bactericidal activity within minutes. Studies with propidium iodide and transmission electron microscopy revealed that peptides damaged the bacterial membrane leading to leakage of cytoplasmic contents and consequently, cell death. A potent synergistic increase in the antibacterial effect of the cell penetrating peptide (KFF)3K was noticed when combined with other peptides and with antibiotics. In addition, all peptides displayed synergistic interactions when combined together. Furthermore, peptides demonstrated good therapeutic indices with minimal toxicity toward mammalian cells. Resistance to peptides did not evolve after 10 passages of S. pseudintermedius at sub-inhibitory concentration. However, the MICs of amikacin and ciprofloxacin increased 32 and 8 fold, respectively; under similar conditions. Taken together, these results support designing of peptide-based therapeutics for combating MRSP infections, particularly for topical application. PMID:25551573
Mohamed, Mohamed F.; Hammac, G. Kenitra; Guptill, Lynn; Seleem, Mohamed N.
Electrochemical evaluation of antibacterial drugs as environment-friendly inhibitors for corrosion of carbon steel in HCl solution
NASA Astrophysics Data System (ADS)
The effect of penicillin G, ampicillin and amoxicillin drugs on the corrosion behavior of carbon steel (ASTM 1015) in 1.0 mol L-1 hydrochloric acid solution was investigated using potentiodynamic polarization, electrochemical impedance spectroscopy (EIS) and electrochemical noise (EN) techniques. The inhibition efficiency was found to increase with increasing inhibitor concentration. The effect of temperature on the rate of corrosion in the absence and presence of these drugs was also studied. Some thermodynamic parameters were computed from the effect of temperature on corrosion and inhibition processes. Adsorption of these inhibitors was found to obey Langmuir adsorption isotherm. There was a case of mixed mode of adsorption here but while penicillin was adsorbed mainly through chemisorption, two other drugs were adsorbed mainly through physisorption. Potentiodynamic polarization measurements indicated that the inhibitors were of mixed type. In addition, this paper suggests that the electrochemical noise (EN) technique under open circuit conditions as the truly noninvasive electrochemical method can be employed for the quantitative evaluation of corrosion inhibition. This was done by using the standard deviation of partial signal (SDPS) for calculation of the amount of noise charges at the particular interval of frequency, thereby obtaining the inhibition efficiency (IE) of an inhibitor. These IE values showed a reasonable agreement with those obtained from potentiodynamic polarization and EIS measurements.
Golestani, Gh.; Shahidi, M.; Ghazanfari, D.
Transport of gemifloxacin, a 4th generation quinolone antibiotic, in the Caco-2 and engineered MDCKII cells, and potential involvement of efflux transporters in the intestinal absorption of the drug.
The oral (po) bioavailability of gemifloxacin mesylate in rats and its possible association with efflux transporters was investigated. The apparent permeabilities (Papp) of gemifloxacin across the Caco-2 cell monolayer were 1.20?▒?0.09?ū?10(-5) cm/s for apical to basal (absorptive) transport, and 2.13?▒?0.6?ū?10(-5) cm/s for basal to apical (secretory) transport for a 5-500 ?M concentration range, suggesting the involvement of a carrier-mediated efflux in the secretory transport. The secretory transport in Caco-2 cells was significantly decreased by MRP2 (MK571) and BCRP (Ko143) inhibitors. The secretory transport was distinct in MDCKII/P-gp, MDCKII/MRP2 and MDCKII/BCRP cells, and the affinity was highest for MRP2, followed by BCRP and P-gp. The efflux was significantly decreased by verapamil and Ko143, but not significantly by MK571. The comparative po bioavailability in rats was increased by the preadministration of Ko143 (four-fold), MK571 (two-fold) and verapamil (two-fold). Efflux transporters appeared to significantly limit the bioavailability of gemifloxacin in rats, suggesting their possible contribution to the low bioavailability of the drug in the human (70%). PMID:23020787
Jin, Hyo-Eon; Song, Boran; Kim, Sang-Bum; Shim, Won-Sik; Kim, Dae-Duk; Chong, Saeho; Chung, Suk-Jae; Shim, Chang-Koo
New poly(ester urea) derived from L-leucine: electrospun scaffolds loaded with antibacterial drugs and enzymes.
Electrospun scaffolds from an amino acid containing poly(ester urea) (PEU) were developed as promising materials in the biomedical field and specifically in tissue engineering applications. The selected poly(ester urea) was obtained with a high yield and molecular weight by reaction of phosgene with a bis(?-aminoacyl)-?,?-diol-diester monomer. The polymer having L-leucine, 1,6-hexanediol and carbonic acid units had a semicrystalline character and relatively high glass transition and melting temperatures. Furthermore it was highly soluble in most organic solvents, an interesting feature that facilitated the electrospinning process and the effective incorporation of drugs with bactericidal activity (e.g. biguanide derivatives such as clorhexidine and polyhexamethylenebiguanide) and enzymes (e.g. ?-chymotrypsin) that accelerated the degradation process. Continuous micro/nanofibers were obtained under a wide range of processing conditions, being diameters of electrospun fibers dependent on the drug and solvent used. Poly(ester urea) samples were degradable in media containing lipases and proteinases but the degradation rate was highly dependent on the surface area, being specifically greater for scaffolds with respect to films. The high hydrophobicity of new scaffolds had repercussions on enzymatic degradability since different weight loss rates were found depending on how samples were exposed to the medium (e.g. forced or non-forced immersion). New scaffolds were biocompatible, as demonstrated by adhesion and proliferation assays performed with fibroblast and epithelial cells. PMID:25492010
DĒaz, Angķlica; del Valle, Luis J; Tugushi, David; Katsarava, Ramaz; PuiggalĒ, Jordi
Use of antibacterial agents in Italian hospitals: a 2004 to 2011 drug utilization survey in the Emilia-Romagna region.
To assess 8-year antibiotic consumption and expenditure in all of the hospitals of Emilia Romagna. The analysis was based on the pharmacy records of each hospital. Antibiotic drug consumption was expressed as DDDs per 100 bed-days used (BDU) and data were analyzed according to ATC classification and to single wards. Expenditure was expressed as Euros per 100 BDU. In the 8-years considered, overall consumption increased by 27% and expenditure by only 3%. Consumption was higher in surgical wards than in medical ones. Penicillins and ?-lactamase inhibitors ranked first, followed by fluoroquinolones and third generation cephalosporins. The results of the study strongly suggest that antibiotic use could be improved by educational interventions to improve clinical practice in hospitals, assessments of guidelines and monitoring of the outcomes of the interventions are needed. PMID:24484182
Buccellato, Elena; Biagi, Chiara; Melis, Mauro; Lategana, Rosalia; Motola, Domenico; Vaccheri, Alberto
Death inducing and cytoprotective autophagy in T-47D cells by two common antibacterial drugs: sulphathiazole and sulphacetamide.
The broad spectrum of the pharmacological effects of sulphonamide family of drugs motivated us to investigate the cellular mechanisms for anti-cancer effects of sulphathiazole and sulphacetamide on T-47D breast cancer cells. Fluorescent microscopy, flow cytometric analysis, caspase-3 activity and DNA fragmentation assays were used to detect apoptosis. The distribution of the cells among different phases of the cell cycle was measured by flow cytometry. The expression of several genes with important roles in some critical cellular pathways including apoptosis, mTOR/AKT pathway and autophagy were determined by real-time RT-PCR analysis. Sulphathiazole and sulphacetamide induced anti-proliferative effects on T-47D cells were independent of apoptosis and cell cycle arrest. The overexpression of critical genes involved in autophagy including ATG5, p53 and DRAM indicated that the main effect of the drug-induced anti-proliferative effects was through induction of autophagy. This process was induced in two different forms, including death inducing and cytoprotective autophagy. Sulphathiazole treatment was followed by higher expression of p53/DRAM and downregulation of Akt/mTOR pathway resulting in death autophagy. In contrast, sulphacetamide treatment lowered expression of p53/DRAM pathway in parallel with upregulation of Akt/mTOR pathway promoting cytoprotective autophagy. The results indicated that autophagy is the main mechanism mediating the anti-cancer effects of sulphathiazole and sulphacetamide on T-47D cells. Alignment of the p53 and DRAM expression along with activation level of Akt survival pathway therefore determines the type of autophagy that occurs. PMID:23450781
Mohammadpour, Raziye; Safarian, Shahrokh; Sheibani, Nader; Norouzi, Saeed; Razazan, Atefeh
Death Inducing and Cytoprotective Autophagy in T-47D Cells by Two Common Antibacterial Drugs: Sulfathiazole and Sulfacetamide
The broad spectrum of the pharmacological effects of sulfonamide family of drugs motivated us to investigate the cellular mechanisms for anti-cancer effects of sulfathiazole and sulfacetamide on T-47D breast cancer cells. Fluorescent microscopy, flow cytometric analysis, caspase-3 activity and DNA fragmentation assays were used to detect apoptosis. The distribution of the cells among different phases of the cell cycle was measured by flow cytometry. The expression of several genes with important roles in some critical cellular pathways including apoptosis, mTOR/AKT pathway and autophagy were determined by real time RT-PCR analysis. Sulfathiazole and sulfacetamide induced anti-proliferative effects on T-47D cells were independent of apoptosis and cell cycle arrest. The overexpression of critical genes involved in autophagy including ATG5, p53 and DRAM indicated that the main effect of the drug-induced anti-proliferative effects was through induction of autophagy. This process was induced in 2 different forms, including death inducing and cytoprotective autophagy. Sulfathiazole treatment was followed by higher expression of p53/DRAM and downregulation of Akt/ mTOR pathway resulting in death autophagy. In contrast, sulfacetamide treatment lowered expression of p53/DRAM pathway in parallel with upregulation of Akt/mTOR pathway promoting cytoprotective autophagy. The results indicated that autophagy is the main mechanism mediating the anti-cancer effects of sulfathiazole and sulfacetamide on T-47D cells. Alignment of the p53 and DRAM expression along with activation level of Akt survival pathway therefore determines the type of autophagy that occurs. PMID:23450781
Mohammadpour, Raziye; Safarian, Shahrokh; Sheibani, Nader; Norouzi, Saeed; Razazan, Atefeh
NSDL National Science Digital Library
In this Science Update, from Science NetLinks, you'll hear one worrisome possibility for the potential environmental effects of common household products. A lot of household products nowadays claim to be antibacterial--containing compounds that kill viruses, bacteria, and other germs on contact. But what happens to these compounds when they get washed down the drain? Science Updates are audio interviews with scientists and are accompanied by a set of questions as well as links to related Science NetLinks lessons and other related resources.
Science Update
Plasmid-Mediated Quinolone Resistance in Clinical Isolates of Escherichia coli from Shanghai, China
Although quinolone resistance usually results from chromosomal mutations, recent studies indicate that quinolone resistance can also be plasmid mediated. The gene responsible, qnr, is distinct from the known quinolone resistance genes and in previous studies seemed to be restricted to Klebsiella pneumoniae and Escherichia coli isolates from the University of Alabama in Birmingham, where this resistance was discovered. In Shanghai,
Minggui Wang; John H. Tran; George A. Jacoby; Yingyuan Zhang; Fu Wang; David C. Hooper
4-(1H)-Quinolones and 1,2,3,4-Tetrahydroacridin-9(10H)-Ones Prevent the Transmission of Plasmodium falciparum to Anopheles freeborni
Malaria kills approximately 1 million people a year, mainly in sub-Saharan Africa. Essential steps in the life cycle of the parasite are the development of gametocytes, as well as the formation of oocysts and sporozoites, in the Anopheles mosquito vector. Preventing transmission of malaria through the mosquito is necessary for the control of the disease; nevertheless, the vast majority of drugs in use act primarily against the blood stages. The study described herein focuses on the assessment of the transmission-blocking activities of potent antierythrocytic stage agents derived from the 4(1H)-quinolone scaffold. In particular, three 3-alkyl- or 3-phenyl-4(1H)-quinolones (P4Qs), one 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ), and one 1,2,3,4-tetrahydroacridin-9(10H)-one (THA) were assessed for their transmission-blocking activity against the mosquito stages of the human malaria parasite (Plasmodium falciparum) and the rodent parasite (P. berghei). Results showed that all of the experimental compounds reduced or prevented the exflagellation of male gametocytes and, more importantly, prevented parasite transmission to the mosquito vector. Additionally, treatment with ICI 56,780 reduced the number of sporozoites that reached the Anopheles salivary glands. These findings suggest that 4(1H)-quinolones, which have activity against the blood stages, can also prevent the transmission of Plasmodium to the mosquito and, hence, are potentially important drug candidates to eradicate malaria. PMID:24080648
Sßenz, Fabißn E.; LaCrue, Alexis N.; Cross, R. Matthew; Maignan, Jordany R.; Udenze, Kenneth O.; Manetsch, Roman
Sequence-motif Detection of NAD(P)-binding Proteins: Discovery of a Unique Antibacterial Drug Target
Many enzymes use nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate (NAD(P)) as essential coenzymes. These enzymes often do not share significant sequence identity and cannot be easily detected by sequence homology. Previously, we determined all distinct locally conserved pyrophosphate-binding structures (3d motifs) from NAD(P)-bound protein structures, from which 1d sequence motifs were derived. Here, we aim to establish the precision of these 3d and 1d motifs to annotate NAD(P)-binding proteins. We show that the pyrophosphate-binding 3d motifs are characteristic of NAD(P)-binding proteins, as they are rarely found in nonNAD(P)-binding proteins. Furthermore, several 1d motifs could distinguish between proteins that bind only NAD and those that bind only NADP. They could also distinguish between NAD(P)-binding proteins from nonNAD(P)-binding ones. Interestingly, one of the pyrophosphate-binding 3d and corresponding 1d motifs was found only in enoyl-acyl carrier protein reductases, which are enzymes essential for bacterial fatty acid biosynthesis. This unique 3d motif serves as an attractive novel drug target, as it is conserved across many bacterial species and is not found in human proteins. PMID:25253464
Hua, Yun Hao; Wu, Chih Yuan; Sargsyan, Karen; Lim, Carmay
Sequence-motif Detection of NAD(P)-binding Proteins: Discovery of a Unique Antibacterial Drug Target
NASA Astrophysics Data System (ADS)
Many enzymes use nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate (NAD(P)) as essential coenzymes. These enzymes often do not share significant sequence identity and cannot be easily detected by sequence homology. Previously, we determined all distinct locally conserved pyrophosphate-binding structures (3d motifs) from NAD(P)-bound protein structures, from which 1d sequence motifs were derived. Here, we aim to establish the precision of these 3d and 1d motifs to annotate NAD(P)-binding proteins. We show that the pyrophosphate-binding 3d motifs are characteristic of NAD(P)-binding proteins, as they are rarely found in nonNAD(P)-binding proteins. Furthermore, several 1d motifs could distinguish between proteins that bind only NAD and those that bind only NADP. They could also distinguish between NAD(P)-binding proteins from nonNAD(P)-binding ones. Interestingly, one of the pyrophosphate-binding 3d and corresponding 1d motifs was found only in enoyl-acyl carrier protein reductases, which are enzymes essential for bacterial fatty acid biosynthesis. This unique 3d motif serves as an attractive novel drug target, as it is conserved across many bacterial species and is not found in human proteins.
Hua, Yun Hao; Wu, Chih Yuan; Sargsyan, Karen; Lim, Carmay
Structures of two N -methylated tricyclic quinolones with antimalarial activity
The crystal structures of two N-methylated tricyclic quinolones were determined. 3-amino-6-methoxy-9-methyl-(1H)pyrazolo[3,4-b]-4-quinolone hydrate, C12H12N4O2?Ę?H2O (1) crystallizes in P-1 with a=11.5078(18)Ā┼, b=13.0614(19)Ā┼, c=9.0860(15)Ā┼, ?=106.229(4)░, ?=108.378(3)░, ?=71.118(3)░ and Z=4, while 2,4-diamino-10-methyl-9-methoxypyrimido[4,5-b]-5-quinolone, C13H13N5O2 (2) crystallizes in P21\\/n with a=10.6643(17)Ā┼, b=10.1114(17)Ā┼, c=11.3185(18)Ā┼, ?=99.351(4)░ and Z=4. Both molecules are essentially planar, including the exocyclic groups. 1 and 2 have moderate antimalarial activity which seems to be
Mario V. Capparelli; Jaime E. Charris; Josķ N. DomĒnguez
Inhibitory activity on DNA gyrase and intracellular accumulation of quinolones: structure-activity relationship of Q-35 analogs.
Q-35, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3- methylaminopiperidine-1-yl)-4-oxyquinoline-3-carboxylic acid, has excellent activity against gram-positive bacteria and inhibits S. aureus gyrase at concentrations more than 10-fold lower than those of other quinolones. In this paper, the effect of the C-7 and C-8 substituents of Q-35 on the inhibitory activity of gyrase purified from S. aureus, M. luteus, E. coli, and P. aeruginosa are described. In addition, intracellular accumulation of Q-35 was examined. The 50% inhibitory concentrations (IC50) of Q-35, 8-fluoro- Q-35, and 8-hydro-Q-35 on DNA gyrase purified from S. aureus were 2.5, 7.8, and 68 micrograms/ml, respectively. The IC50 on gyrase from P. aeruginosa were 11, 5.2, and 17 micrograms/ml, respectively. It is concluded that the introduction of a methoxy group into the 8 position of the quinolone leads to greater antibacterial activity against gram-positive bacteria. The concentrations of Q-35 which accumulated in S. aureus and E. coli were almost equal to ciprofloxacin, but in P. aeruginosa, Q-35 was lower than ciprofloxacin. PMID:8000379
Ito, T; Kojima, K; Koizumi, K; Nagano, H; Nishino, T
Longitudinal surveillance of outpatient quinolone antimicrobial use in Canada
INTRODUCTION: Because antimicrobial use is commonly associated with the development of antimicrobial resistance, monitoring the volume and patterns of use of these agents is important. OBJECTIVE: To assess the use of quinolone antimicrobials within Canadian provinces over time. METHODS: Antimicrobial prescribing data collected by IMS Health Canada were acquired from the Canadian Integrated Program for Antimicrobial Resistance Surveillance and the Canadian Committee for Antimicrobial Resistance, and were used to calculate two yearly metrics: prescriptions per 1000 inhabitant-days and the mean defined daily doses (DDDs) per prescription. These measures were used to produce linear mixed models to assess differences among provinces and over time, while accounting for repeated measurements. RESULTS: The quinolone class of antimicrobials is used similarly among Canadian provinces. Year-to-year increases in quinolone prescribing occurred from 1995 to 2010, with a levelling off in the latter years. Year-to-year decreases in the DDDs per prescription were found to be significant from 2000 to 2010. DISCUSSION: Although the overall use of antimicrobials differs significantly among Canadian provinces, the use of the quinolone class does not vary at the provincial level. Results suggest that prescribing of ciprofloxacin may be a potential target for antimicrobial stewardship programs; however, decreases in the average DDDs per prescription suggest continued uptake of appropriate treatment guidelines. PMID:24855478
Glass-Kaastra, Shiona K; Finley, Rita; Hutchinson, Jim; Patrick, David M; Weiss, Karl; Conly, John
Analysis and prediction of antibacterial peptides
Background Antibacterial peptides are important components of the innate immune system, used by the host to protect itself from different types of pathogenic bacteria. Over the last few decades, the search for new drugs and drug targets has prompted an interest in these antibacterial peptides. We analyzed 486 antibacterial peptides, obtained from antimicrobial peptide database APD, in order to understand the preference of amino acid residues at specific positions in these peptides. Results It was observed that certain types of residues are preferred over others in antibacterial peptides, particularly at the N and C terminus. These observations encouraged us to develop a method for predicting antibacterial peptides in proteins from their amino acid sequence. First, the N-terminal residues were used for predicting antibacterial peptides using Artificial Neural Network (ANN), Quantitative Matrices (QM) and Support Vector Machine (SVM), which resulted in an accuracy of 83.63%, 84.78% and 87.85%, respectively. Then, the C-terminal residues were used for developing prediction methods, which resulted in an accuracy of 77.34%, 82.03% and 85.16% using ANN, QM and SVM, respectively. Finally, ANN, QM and SVM models were developed using N and C terminal residues, which achieved an accuracy of 88.17%, 90.37% and 92.11%, respectively. All the models developed in this study were evaluated using five-fold cross validation technique. These models were also tested on an independent or blind dataset. Conclusion Among antibacterial peptides, there is preference for certain residues at N and C termini, which helps to demarcate them from non-antibacterial peptides. Both the termini play a crucial role in imparting the antibacterial property to these peptides. Among the methods developed, SVM shows the best performance in predicting antibacterial peptides followed by QM and ANN, in that order. AntiBP (Antibacterial peptides) will help in discovering efficacious antibacterial peptides, which we hope will prove to be a boon to combat the dreadful antibiotic resistant bacteria. A user friendly web server has also been developed to help the biological community, which is accessible at . PMID:17645800
Lata, Sneh; Sharma, BK; Raghava, GPS
Cleavable-Complex Formation by Wild-Type and Quinolone-Resistant Streptococcus pneumoniae Type II Topoisomerases Mediated by Gemifloxacin and Other Fluoroquinolones
Gemifloxacin is a recently developed fluoroquinolone with potent activity against Streptococcus pneumoniae. We show that the drug is more active than moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin against S. pneumoniae strain 7785 (MICs, 0.03 to 0.06 g\\/ml versus 0.25, 0.25, 1, and 1 to 2 g\\/ml, respectively) and against isogenic quinolone-resistant gyrA-parC mutants (MICs, 0.5 to 1 g\\/ml versus 2 to
Genoveva Yague; Julia E. Morris; Xiao-Su Pan; Katherine A. Gould; L. Mark Fisher
Synthesis, Characterization, and Antibacterial Activities of Novel Sulfonamides Derived through Condensation of Amino Group Containing Drugs, Amino Acids, and Their Analogs
Novel sulfonamides were developed and structures of the new products were confirmed by elemental and spectral analysis (FT-IR, ESI-MS, 1HNMR, and 13CNMR). In vitro, developed compounds were screened for their antibacterial activities against medically important gram (+) and gram (?) bacterial strains, namely, S. aureus, B. subtilis, E. coli, and K. pneumoniae. The antibacterial activities have been determined by measuring MIC values (?g/mL) and zone of inhibitions (mm). Among the tested compounds, it was found that compounds 5a and 9a have most potent activity against E. coli with zone of inhibition: 31 ▒ 0.12?mm (MIC: 7.81??g/mL) and 30 ▒ 0.12?mm (MIC: 7.81??g/mL), respectively, nearly as active as ciprofloxacin (zone of inhibition: 32 ▒ 0.12?mm). In contrast, all the compounds were totally inactive against the gram (+) B. subtilis.
Abdul Qadir, Muhammad; Ahmed, Mahmood; Iqbal, Muhammad
Computational methods to identify new antibacterial targets.
The development of resistance to all current antibiotics in the clinic means there is an urgent unmet need for novel antibacterial agents with new modes of action. One of the best ways of finding these is to identify new essential bacterial enzymes to target. The advent of a number of in silico tools has aided classical methods of discovering new antibacterial targets, and these programs are the subject of this review. Many of these tools apply a cheminformatic approach, utilizing the structural information of either ligand or protein, chemogenomic databases, and docking algorithms to identify putative antibacterial targets. Considering the wealth of potential drug targets identified from genomic research, these approaches are perfectly placed to mine this rich resource and complement drug discovery programs. PMID:24974974
McPhillie, Martin J; Cain, Ricky M; Narramore, Sarah; Fishwick, Colin W G; Simmons, Katie J
In vitro antibacterial spectrum of a new broad-spectrum 8-methoxy fluoroquinolone, gatifloxacin.
The in vitro antibacterial spectrum of gatifloxacin was compared with those of ciprofloxacin and ofloxacin. Gatifloxacin was two- to four-fold more potent than comparator quinolones against staphylococci, streptococci, pneumococci and enterococci (gatifloxacin MIC90s, < or =1 mg/L, except 4 mg/L against methicillin-resistant Staphylococcus aureus and Enterococcus faecium). Gatifloxacin was two-fold less potent than ciprofloxacin, and the same as or two-fold more potent than ofloxacin against Enterobacteriaceae (MIC90s, 0.06-0.5 mg/L against most members of the Enterobacteriaceae and < or =1 mg/L against Proteus/Morganella spp.). Relative to the comparator quinolones, gatifloxacin was two- to four-fold more potent against Providencia spp., and had good potency against Acinetobacter spp. (MIC90s, 0.25-1 mg/L). Gatifloxacin and ofloxacin had similar anti-pseudomonal potency, with corresponding MIC90s of 4, 8 and 0.25 mg/L for Pseudomonas aeruginosa, Pseudomonas fluorescens and Pseudomonas stutzeri, while ciprofloxacin had two- to eight-fold more potency. The three quinolones were equipotent against Burkholderia cepacia (MIC90s, 8 mg/L), but gatifloxacin was two-fold more potent against Stenotrophomonas maltophilia (MIC90, 4 mg/L). Gatifloxacin was highly potent (MIC90s, 0.03-0.06 mg/L) against Haemophilus influenzae, Legionella spp., Helicobacter pylori and had at least eight-fold better anti-chlamydial and anti-mycoplasma potency (gatifloxacin MIC90s, 0.13 mg/L). The higher quinolone MICs for ureaplasma (MIC90s, 4-8 mg/L) may be due to the acidic pH of the ureaplasma test medium, which antagonizes quinolones. Like other quinolones, gatifloxacin had poor potency against Mycobacterium avium-intracellulare, though it was eight- to 16-fold more potent against Mycobacterium tuberculosis (MIC90, 0.25 mg/L). Of the three quinolones, only gatifloxacin had activity against Bacteroides fragilis and Clostridium difficile. In summary, gatifloxacin is a broad-spectrum 8-methoxy fluoroquinolone that is more potent than ciprofloxacin and ofloxacin against Gram-positive bacteria, chlamydia, mycoplasma, mycobacteria and anaerobes. PMID:10747819
Fung-Tomc, J; Minassian, B; Kolek, B; Washo, T; Huczko, E; Bonner, D
Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria
There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase (Plasmodium falciparum NDH2) and cytochrome bc1. Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimidine metabolism and parasite death. Several analogs also display activity against liver-stage parasites (Plasmodium cynomolgi) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium berghei mouse malaria model associated with favorable pharmacokinetic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria. PMID:22566611
Biagini, Giancarlo A.; Fisher, Nicholas; Shone, Alison E.; Mubaraki, Murad A.; Srivastava, Abhishek; Hill, Alisdair; Antoine, Thomas; Warman, Ashley J.; Davies, Jill; Pidathala, Chandrakala; Amewu, Richard K.; Leung, Suet C.; Sharma, Raman; Gibbons, Peter; Hong, David W.; Pacorel, Bķnķdicte; Lawrenson, Alexandre S.; Charoensutthivarakul, Sitthivut; Taylor, Lee; Berger, Olivier; Mbekeani, Alison; Stocks, Paul A.; Nixon, Gemma L.; Chadwick, James; Hemingway, Janet; Delves, Michael J.; Sinden, Robert E.; Zeeman, Anne-Marie; Kocken, Clemens H. M.; Berry, Neil G.; OÆNeill, Paul M.; Ward, Stephen A.
Phytochemical constituents of Allium porrum leaf extracts and its antibacterial potentialities were evaluated using different solvents. Phytochemical screening of the different extracts showed that leaves contains important compounds such as amino acid with sulphate, carbohydrates, Phenols, Proteins, flavonoids, alkaloids, steroids, Tannins and saponin. Aqueous, methanol and acetone extracts of plant leaves were used for assessing antibacterial activity against Salmonella typhi, Klebsiella pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa and Proteus vulgaris by agar well diffusion method. The present study demonstrated that the aqueous, methanolic, acetone extracts of A. porrum consists different phytochemical components thus exhibit variations in the antibacterial activity. These promissory extracts open the prospect of finding new clinically effective antibacterial compounds.
T. Ushadevi; R. Sathya; R. Shanmugapriya; K. Anandhi
Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)
A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17?000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure¢activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC50 against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc1, and studies to determine the potential advantage of this dual-targeting effect are in progress. PMID:22364416
Simple and sensitive determination of five quinolones in food by liquid chromatography with fluorescence detection
A simple and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the determination of five different quinolones: enrofloxacin, ciprofloxacin, sarafloxacin, oxolinic acid and flumequine in pork and salmon muscle. The method includes one extraction and clean-up step for the five quinolones together which are detected in two separated HPLC runs by means of their fluorescence. The proposed analytical
Macarena Ramos; Angela Aranda; Elena Garcia; Thea Reuvers; Henny Hooghuis
Contribution of Topoisomerase IV Mutation to Quinolone Resistance in Mycoplasma genitalium
The mechanism of quinolone resistance in Mycoplasma genitalium remains poorly understood due to difficulties with in vitro culture, especially of clinical isolates. In this study, to confirm the association between mutations in topoisomerases and antimicrobial susceptibilities to quinolones, ciprofloxacin-resistant mutant strains were selected using the cultivable type strain ATCC 33530. Sequence analysis revealed that the mutant strains harbored mutations in topoisomerase IV: Gly81Cys in ParC, Pro261Thr in ParC, or Asn466Lys in ParE. The MICs of all quinolones tested against the mutant strains were 2- to 16-fold higher than those against the wild-type strain. No cross-resistance was observed with macrolides or tetracyclines. We determined the inhibitory activities of quinolones against DNA gyrase and topoisomerase IV in order to investigate the correlation between antimicrobial susceptibility and inhibitory activity against the target enzymes, considered the primary targets of quinolones. Furthermore, using enzymatic analysis, we confirmed that Gly81Cys in the ParC quinolone resistance-determining region (QRDR) contributed to quinolone resistance. This is the first study to isolate quinolone-resistant mutant strains of M. genitalium harboring substitutions in the parC or parE gene in vitro and to measure the inhibitory activities against the purified topoisomerases of M. genitalium. PMID:23357772
Takei, Masaya; Kishii, Ryuta; Yasuda, Mitsuru; Deguchi, Takashi
In vitro evaluation of antibacterial and immunomodulatory activities of Pelargonium reniforme, Pelargonium sidoides and the related herbal drug preparation EPs 7630.
The importance of Pelargonium species, most notably Pelargonium reniforme and Pelargonium sidoides, in traditional medicine in the Southern African region is well documented. Nowadays, a modern aqueous-ethanolic formulation of the roots of P. sidoides (EPs) 7630) is successfully employed for the treatment of ear, nose and throat disorders as well as respiratory tract infections. To provide a scientific basis of its present utilization in phytomedicine, EPs 7630, extracts and isolated constituents of the titled Pelargoniums with emphasis on P. sidoides were evaluated for antibacterial activity and for their effects on nonspecific immune functions. The samples exhibited merely moderate direct antibacterial capabilities against a spectrum of Gram-positive and Gram-negative bacteria. Functional bioassays including an in vitro model for intracellular diseases, a fibroblast-lysis assay (tumour necrosis factor (TNF) activity), a fibroblast-virus protection assay (IFN activity) and a biochemical assay for nitric oxides revealed significant immunomodulatory properties. Gene expression experiments (iNOS, IFN-alpha, IFN-gamma, TNF-alpha, Interleukin (IL)-1, IL-10, IL12, IL-18) not only confirmed functional data, they also clearly showed differences in the response of infected macrophages when compared to that of noninfected cells. ELISA confirmed the protein production of TNF-alpha, IL-1alpha and IL-12, while FACS analyses reaffirmed the cytokines IL-1alpha and IL-12 at the singular cell level. The current data provide convincing support for the improvement of immune functions at various levels, hence, validating the medicinal uses of EPs 7630. Despite considerable efforts, the remedial effects cannot yet be related to a chemically defined principle. PMID:17188480
Kolodziej, Herbert; Kiderlen, Albrecht F
Antibacterial kaolinite/urea/chlorhexidine nanocomposites: Experiment and molecular modelling
NASA Astrophysics Data System (ADS)
Clay minerals are commonly used materials in pharmaceutical production both as inorganic carriers or active agents. The purpose of this study is the preparation and characterization of clay/antibacterial drug hybrids which can be further included in drug delivery systems for treatment oral infections. Novel nanocomposites with antibacterial properties were successfully prepared by ion exchange reaction from two types of kaolinite/urea intercalates and chlorhexidine diacetate. Intercalation compounds of kaolinite were prepared by reaction with solid urea in the absence of solvents (dry method) as well as with urea aqueous solution (wet method). The antibacterial activity of two prepared samples against Enterococcus faecalis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa was evaluated by finding the minimum inhibitory concentration (MIC). Antibacterial studies of both samples showed the lowest MIC values (0.01%, w/v) after 1 day against E. faecalis, E. coli and S. aureus. A slightly worse antibacterial activity was observed against P. aeruginosa (MIC 0.12%, w/v) after 1 day. Since samples showed very good antibacterial activity, especially after 1 day of action, this means that these samples can be used as long-acting antibacterial materials. Prepared samples were characterized by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). The experimental data are supported by results of molecular modelling.
HoleÜovß, Sylva; ValßÜkovß, Marta; Hlavß?, Dominik; Madejovß, Jana; SamlĒkovß, Magda; Tokarsk², JonßÜ; Pazdziora, Erich
Antibacterial activities of multi drug resistant Myroides odoratimimus bacteria isolated from adult flesh flies (Diptera: sarcophagidae) are independent of metallo beta-lactamase gene
Flesh flies (Diptera: Sarcophagidae) are well known cause of myiasis and their gut bacteria have never been studied for antimicrobial activity against bacteria. Antimicrobial studies of Myroides spp. are restricted to nosocomial strains. A Gram-negative bacterium, Myroides sp., was isolated from the gut of adult flesh flies (Sarcophaga sp.) and submitted to evaluation of nutritional parameters using Biolog GN, 16S rRNA gene sequencing, susceptibility to various antimicrobials by disc diffusion method and detection of metallo ?-lactamase genes (TUS/MUS). The antagonistic effects were tested on Gram-negative and Gram-positive bacteria isolated from human clinical specimens, environmental samples and insect mid gut. Bacterial species included were Aeromonas hydrophila, A. culicicola, Morganella morganii subsp. sibonii, Ochrobactrum anthropi, Weissella confusa, Escherichia coli, Ochrobactrum sp., Serratia sp., Kestersia sp., Ignatzschineria sp., Bacillus sp. The Myroides sp. strain was resistant to penicillin-G, erythromycin, streptomycin, amikacin, kanamycin, gentamycin, ampicillin, trimethoprim and tobramycin. These strain showed antibacterial action against all bacterial strains except W. confusa, Ignatzschineria sp., A. hydrophila and M. morganii subsp. sibonii. The multidrug resistance of the strain was similar to the resistance of clinical isolates, inhibiting growth of bacteria from clinical, environmental and insect gut samples. The metallo ?-lactamase (TUS/MUS) genes were absent, and resistance due to these genes was ruled out, indicating involvement of other secretion machinery. PMID:24031236
Dharne, M.S.; Gupta, A.K.; Rangrez, A.Y.; Ghate, H.V.; Patole, M.S.; Shouche, Y.S.
Antibacterials in Household Products
... other antimicrobials. Studies comparing families who used antibacterial soap to families who did not have found no ... to infection. For most purposes, washing with regular soap and rinsing with running water, followed by thorough ...
InĀvitro antibacterial activity of medicinal plant extracts against Escherichia coli strains from human clinical specimens and interactions with antimicrobial drugs.
The biological properties of medicinal plants have been documented worldwide for many centuries. We aimed to evaluate interactions between crude extracts from Psidium guajava, Zingiber officinale, Cymbopogon citratus, Caryophyllus aromaticus, Mikania glomerata and Allium sativum samples and antimicrobial drugs against Escherichia coli strains. The susceptibility test performed was disc diffusion, and crude extracts were diluted (%v/v) into M³ller-Hinton agar (MHA) at one quarter of the minimal inhibitory concentration for 90% (MIC(90%)) of E. coli strains found previously. Synergistic interactions were observed between C. citratus and polymyxin, and A. sativum extracts and gentamicin. The crude A. sativum extract was the only one that did not show any antagonism with the antimicrobial drugs. The results thus showed the potential use of these medicinal plants against E. coli strains, although antagonism with antimicrobial drugs is a negative aspect in the combined therapy of infectious diseases caused by E. coli. PMID:22011190
Ushimaru, P I; Barbosa, L N; Fernandes, A A H; Di Stasi, L C; Fernandes, A
Interaction of Bacteriocin-Capped Silver Nanoparticles with Food Pathogens and Their Antibacterial Effect
With the emergence of multiple-drug-resistant pathogens, the antibacterial property of silver in colloidal form has emerged as a potential candidate for combating infectious diseases. A combination of antibacterial agents along with nanosilver could prove to be more potent due to broadened antibacterial spectrum with possibly lower doses. In the present study, a facile single-step green method of synthesizing silver nanoparticles
Tarun Kumar Sharma; Mahak Sapra; Aradhana Chopra; Rekha Sharma; Supriya Deepak Patil; Ravinder Kumar Malik; Ranjana Pathania; Naveen Kumar Navani
Molecular Investigation of Quinolone Resistance of Quinolone Resistance-Determining Region in Streptococcus pneumoniae Strains Isolated from Iran Using Polymerase Chain Reaction¢Restriction Fragment Length Polymorphism Method
Objectives The resistance of Streptococcus pneumoniae to the recently available antibiotic treatment has been a growing problem. The aim of the study was to determine the quinolone-resistant strains and detect the presence of mutations in the quinolone resistance-determining regions of the gyrA, parE, and parC genes. Methods In this study, for the first time in Iran, the polymerase chain reaction¢restriction fragment length polymorphism (PCR-RFLP) method was used to investigate the presence of mutations at quinolone resistance-determining regions of topoisomerase IV and DNA gyrase on 82 S. pneumoniae strains, among them 45 clinical samples were from patients and 37 from healthy carriers (control group). Results In clinical samples, 34 (75.56%) strains contained mutations in the parC gene, 31 (68.89%) carried mutations in the gyrA gene, and 14 (31.11%) had parE gene mutations. Antibiotic susceptibility test was performed using the CLSI (Clinical and Laboratory Standards Institute) criteria on three different generations of quinolone family, with nalidixic acid (82.22%) showing the highest resistance and levofloxacin (42.22%) the least resistance. Conclusion Results indicated that there is a significant correlation between quinolone resistance development and mutations in the parE gene as well as in the parC and gyrA genes. PMID:25389509
Kargar, Mohammad; Moein Jahromi, Fataneh; Doosti, Abbas; Handali, Somayeh
Vitiquinolone--a quinolone alkaloid from Hibiscus vitifolius Linn.
Phytochemical investigations of the powdered root of Hibiscus vitifolius Linn. (Malvaceae) was extracted successively with n-hexane and chloroform. Analysis of the n-hexane extract by GC-MS led to the identification of twenty-six components by comparison of their mass spectra with GC-MS library data. A novel quinolone alkaloid, vitiquinolone (5) together with eight known compounds viz. ?-Amyrin acetate (1), n-octacosanol (2), ?-Amyrin (3), stigmasterol (4), xanthyletin (6), alloxanthoxyletin (7), xanthoxyletin (8) and betulinic acid (9) were isolated from chloroform extract by column chromatography over silica gel. The structure of vitiquinolone was established on the basis of spectroscopic methods including UV, IR, 1D, 2D NMR and ESI-MS. The known compounds were identified on the basis of their physical and spectroscopic data as reported in the literature. PMID:24128571
Ramasamy, D; Saraswathy, A
Antigiardial activity of novel triazolyl-quinolone-based chalcone derivatives: when oxygen makes the difference
Giardiasis is a common diarrheal disease worldwide caused by the protozoan parasite Giardia intestinalis. It is urgent to develop novel drugs to treat giardiasis, due to increasing clinical resistance to the gold standard drug metronidazole (MTZ). New potential antiparasitic compounds are usually tested for their killing efficacy against G. intestinalis under anaerobic conditions, in which MTZ is maximally effective. On the other hand, though commonly regarded as an æanaerobic pathogen,Æ G. intestinalis is exposed to relatively high O2 levels in vivo, living attached to the mucosa of the proximal small intestine. It is thus important to test the effect of O2 when searching for novel potential antigiardial agents, as outlined in a previous study [Bahadur et al. (2014) Antimicrob. Agents Chemother. 58, 543]. Here, 45 novel chalcone derivatives with triazolyl-quinolone scaffold were synthesized, purified, and characterized by high resolution mass spectrometry, 1H and 13C nuclear magnetic resonance and infrared spectroscopy. Efficacy of the compounds against G. intestinalis trophozoites was tested under both anaerobic and microaerobic conditions, and selectivity was assessed in a counter-screen on human epithelial colorectal adenocarcinoma cells. MTZ was used as a positive control in the assays. All the tested compounds proved to be more effective against the parasite in the presence of O2, with the exception of MTZ that was less effective. Under anaerobiosis eighteen compounds were found to be as effective as MTZ or more (up to three to fourfold); the same compounds proved to be up to >100-fold more effective than MTZ under microaerobic conditions. Four of them represent potential candidates for the design of novel antigiardial drugs, being highly selective against Giardia trophozoites. This study further underlines the importance of taking O2 into account when testing novel potential antigiardial compounds. PMID:25904901
Bahadur, Vijay; Mastronicola, Daniela; Singh, Amit K.; Tiwari, Hemandra K.; Pucillo, Leopoldo P.; Sarti, Paolo; Singh, Brajendra K.; GiuffrĶ, Alessandro
Differentiation in Quinolone Resistance by Virulence Genotype in Pseudomonas aeruginosa
Pseudomonas aeruginosa is a leading pathogen that has become increasingly resistant to the fluoroquinolone antibiotics due to widespread prescribing. Adverse outcomes have been shown for patients infected with fluoroquinolone-resistant strains. The type III secretion system (TTSS) is a major virulence determinant during acute infections through the injection of effector toxins into host cells. Most strains exhibit a unique TTSS virulence genotype defined by the presence of either exoS or exoU gene encoding two of the effector toxins, ExoS and ExoU, respectively. Specific TTSS effector genotype has been shown previously to differentially impact virulence in pneumonia. In this study, we examined the relationship between TTSS effector genotype and fluoroquinolone resistance mechanisms in a collection of 270 respiratory isolates. We found that a higher proportion of exoU+ strains were fluoroquinolone-resistant compared to exoS+ strains (63% vs 49%, p?=?0.03) despite its lower overall prevalence (38% exoU+ vs 56% exoS+). Results from sequencing the quinolone resistance determining regions (QRDRs) of the 4 target genes (gyrA, gyrB, parC, parE) indicated that strains containing the exoU gene were more likely to acquire ?2 mutations than exoS+ strains at MICs ?8 Ąg/ml (13% vs none) and twice as likely to have mutations in both gyrA and parC than exoS+ strains (48% vs 24% p?=?0.0439). Our findings indicate that P. aeruginosa strains differentially develop resistance-conferring mutations that correlate with TTSS effector genotype and the more virulent exoU+ subpopulation. Differences in mutational processes by virulence genotype that were observed suggest co-evolution of resistance and virulence traits favoring a more virulent genotype in the quinolone-rich clinical environment. PMID:22905192
Agnello, Melissa; Wong-Beringer, Annie
Differentiation in quinolone resistance by virulence genotype in Pseudomonas aeruginosa.
Pseudomonas aeruginosa is a leading pathogen that has become increasingly resistant to the fluoroquinolone antibiotics due to widespread prescribing. Adverse outcomes have been shown for patients infected with fluoroquinolone-resistant strains. The type III secretion system (TTSS) is a major virulence determinant during acute infections through the injection of effector toxins into host cells. Most strains exhibit a unique TTSS virulence genotype defined by the presence of either exoS or exoU gene encoding two of the effector toxins, ExoS and ExoU, respectively. Specific TTSS effector genotype has been shown previously to differentially impact virulence in pneumonia. In this study, we examined the relationship between TTSS effector genotype and fluoroquinolone resistance mechanisms in a collection of 270 respiratory isolates. We found that a higher proportion of exoU+ strains were fluoroquinolone-resistant compared to exoS+ strains (63% vs 49%, p = 0.03) despite its lower overall prevalence (38% exoU+ vs 56% exoS+). Results from sequencing the quinolone resistance determining regions (QRDRs) of the 4 target genes (gyrA, gyrB, parC, parE) indicated that strains containing the exoU gene were more likely to acquire ? 2 mutations than exoS+ strains at MICs ? 8 Ąg/ml (13% vs none) and twice as likely to have mutations in both gyrA and parC than exoS+ strains (48% vs 24% p = 0.0439). Our findings indicate that P. aeruginosa strains differentially develop resistance-conferring mutations that correlate with TTSS effector genotype and the more virulent exoU+ subpopulation. Differences in mutational processes by virulence genotype that were observed suggest co-evolution of resistance and virulence traits favoring a more virulent genotype in the quinolone-rich clinical environment. PMID:22905192
Agnello, Melissa; Wong-Beringer, Annie
Prediction of Quinolone Activity against Mycobacterium avium by Molecular Topology and Virtual Computational Screening
We conducted a quantitative structure-activity relationship study using a database of 158 quinolones previously tested against Mycobacterium avium-M. intracellulare complex in order to develop a model capable of predicting the activity of new quinolones against the M. avium-M. intracellulare complex in vitro. Topological indices were used as structural descriptors and were related to anti-M. avium-M. intracellulare complex activity by using
Investigation of the antibacterial activity of pioglitazone
Purpose: To evaluate the antibacterial potential of pioglitazone, a member of the thiazolidinediones class of drugs, against Gram-positive (Streptococcus pneumoniae) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria. Methods: Susceptibility testing was done using the antibiotic disk diffusion method and the minimal inhibitory concentration (MIC) of pioglitazone was measured according to the broth micro incubation standard method. Results: Pioglitazone induced a dose-dependent antibacterial activity in which the optimal concentration was 80 ?M. Furthermore, results indicated that while E. coli was sensitive (MIC = 31.25 ▒ 3.87 mg/L) to pioglitazone-induced cytotoxicity, S. pneumoniae and K. pneumoniae were resistant (MIC = 62.5 ▒ 3.77 mg/L and MIC = 62.5 ▒ 4.14 mg/L, respectively). Moreover, pretreatment of bacteria with a suboptimal concentration of pioglitazone (40 ?M) before adding amoxicillin, cephalexin, co-trimoxazole, or ciprofloxacin enhanced the antibacterial activity of all agents except co-trimoxazole. This enhancing effect was particularly seen against K. pneumoniae. Conclusion: These results indicate the possibility of a new and potentially important pioglitazone effect and the authorsÆ ongoing studies aim to illustrate the mechanism(s) by which this antibacterial effect is induced. PMID:22087061
Masadeh, Majed M; Mhaidat, Nizar M; Al-Azzam, Sayer I; Alzoubi, Karem H
Nutritional and antibacterial treatments of live food organisms : the influence on survival,
Nutritional and antibacterial treatments of live food organisms : the influence on survival, growth-Pķe-sur-Nivelle, F 64310 Ascain Summary After ingestion of nutrients and/or antibacterial drug, live food organisms the live food organisms had not been enriched, survival on day 45 was between 5 and 14 p. 100, and the mean
Paris-Sud XI, Universitķ de
Optical control of antibacterial activity
NASA Astrophysics Data System (ADS)
Bacterial resistance is a major problem in the modern world, stemming in part from the build-up of antibiotics in the environment. Novel molecular approaches that enable an externally triggered increase in antibiotic activity with high spatiotemporal resolution and auto-inactivation are highly desirable. Here we report a responsive, broad-spectrum, antibacterial agent that can be temporally activated with light, whereupon it auto-inactivates on the scale of hours. The use of such a æsmartÆ antibiotic might prevent the build-up of active antimicrobial material in the environment. Reversible optical control over active drug concentration enables us to obtain pharmacodynamic information. Precisely localized control of activity is achieved, allowing the growth of bacteria to be confined to defined patterns, which has potential for the development of treatments that avoid interference with the endogenous microbial population in other parts of the organism.
Velema, Willem A.; van der Berg, Jan Pieter; Hansen, Mickel J.; Szymanski, Wiktor; Driessen, Arnold J. M.; Feringa, Ben L.
Evaluation of antibacterial activity and cytocompatibility of ciprofloxacin loaded gelatin-hydroxyapatite scaffolds as a local drug delivery system for osteomyelitis treatment.
Surgical debridement of the dead bone and subsequent systemic antibiotic therapy is often ineffective in eliminating Staphylococcus aureus infections in osteomyelitic patients. The recurrence of S. aureus infection is mainly due to the intracellular growth of bacterial colonies within osteoblast cells that protect the organism from extracellular host defences and/or antibiotic therapy. In this study, porous gelatin-hydroxyapatite (HAP) scaffolds with various amounts of ciprofloxacin (1, 2, 5, and 10?wt%) were fabricated by freeze-drying technique and the release of the antibiotic was characterized, as was the efficacy of the released antibiotic against methicillin-sensitive and methicillin-resistant S. aureus. Furthermore, the impact of the released antibiotic on the viability and osteogenic differentiation of human adipose-derived mesenchymal stem cells (ADMSCs) cultured on the scaffolds were assessed. Finally, the efficacy of the released ciprofloxacin to enter the cells and abate intracellularly located S. aureus was evaluated. All the groups of CGHA scaffolds displayed sustained release of ciprofloxacin against S. aureus for 60 days above the minimum inhibitory concentration for the target species with zero-order kinetics and Korsmeyer-Peppas models. While comparing, the released antibiotic from CGHA5 scaffolds was found to be effective at reducing S. aureus through the study period, without detrimental effects on human ADMSC viability or osteogenic potential. When stem cells internalized with S. aureus were cultured onto the drug-loaded scaffolds, a significant reduction in the colony count of internalized bacteria was observed, resulting in the osteogenic differentiation capability of those cells. Our results clearly demonstrate that the ciprofloxacin incorporated gelatin-HAP scaffolds, which were cytocompatible and could target both intracellular and extracellular S. aureus, defining its potential to be used as local drug delivery system. PMID:25567452
Krishnan, Amit G; Jayaram, Lakshmi; Biswas, Raja; Nair, Manitha
Characterization of quinolone resistance in Salmonella enterica serovar Indiana from chickens in China1.
The aim of this study was to characterize the quinolone resistance of Salmonella enterica serovar Indiana isolated from chickens in China. A total of 293 Salmonella strains were isolated from chicken farms and slaughterhouses in Shandong province of China, and 130 (44.4%) were characterized as Salmonella enterica Indiana (chicken farms, n = 52 strains; slaughter houses, n = 78 strains). All isolate serotypes were tested with the Kauffmann-White classification system and examined for susceptibility to the quinolones: nalidixic acid, enrofloxacin, norfloxacin, and ciprofloxacin. The resistance of the Salmonella Indiana strains to nalidixic acid, enrofloxacin, norfloxacin, and ciprofloxacin were 100, 73.1, 71.2, and 82.7%, and 100, 59.0, 79.5, and 80.2%, respectively. Selected quinolone resistant strains were evaluated for mutations in genes (gyrA, gyrB, parC, and marA) by DNA sequencing. The gyrA mutation was found in all isolates, the parC mutation was only found in some isolates, and the gyrB and marA mutations were not observed. Quinolone resistance was evaluated in the representative isolates by screening for the quinolone resistance determinants, qnrA, qnrB, qnrS, qepA, and aac (6?')-Ib-cr using PCR technology. The quinolone resistance determinants in Salmonella, qnrA, qnrB, qnrS, and qepA were negative by PCR, but aac(6?')-Ib-cr had high detection rates of 90.4 and 96.2% in chicken farms and slaughterhouses, respectively. Salmonella Indiana containing the gyrA mutation was prevalent in farms and slaughterhouses and possessed a high frequency of the quinolone resistance determinant aac(6?')-Ib-cr. These bacteria may have originated from the same source. PMID:25701209
Lu, Yan; Zhao, Hongyu; Liu, Yuqi; Zhou, Xuping; Wang, Jinyuan; Liu, Tiantian; Beier, Ross C; Hou, Xiaolin
Antibacterial targets in fatty acid biosynthesis.
The fatty acid biosynthesis pathway is an attractive but still largely unexploited target for the development of new antibacterial agents. The extended use of the antituberculosis drug isoniazid and the antiseptic triclosan, which are inhibitors of fatty acid biosynthesis, validates this pathway as a target for antibacterial development. Differences in subcellular organization of the bacterial and eukaryotic multienzyme fatty acid synthase systems offer the prospect of inhibitors with host versus target specificity. Platensimycin, platencin, and phomallenic acids, newly discovered natural product inhibitors of the condensation steps in fatty acid biosynthesis, represent new classes of compounds with antibiotic potential. An almost complete catalog of crystal structures for the enzymes of the type II fatty acid biosynthesis pathway can now be exploited in the rational design of new inhibitors, as well as the recently published crystal structures of type I FAS complexes. PMID:17707686
Wright, H Tonie; Reynolds, Kevin A
High levels of multiresistance in quinolone resistant urinary tract isolates of Escherichia coli from Norway; a non clonal phenomen?
Background The problem of emerging ciprofloxacin resistance is compounded by its frequent association with multiresistance, the reason for which is not fully understood. In this study we compare multiresistance, clonal similarities and phylogenetic group in urinary tract isolates of Escherichia coli sensitive and resistant to the quinolone antimicrobials nalidixic acid and ciprofloxacin. Results Quinolone resistant isolates were more resistant to non-quinolone antibiotics than sensitive isolates, with resistance to ampicillin, mecillinam, sulphonamide, trimethoprim, tetracycline, kanamycin and chloramphenicol significantly increased. Fifty-one percent of quinolone-resistant isolates were multiresistant. Although multiresistance was most prevalent (63%) in isolates showing high-level ciprofloxacin resistance, it was still highly prevalent (41%) in nalidixic acid resistant isolates with low-level ciprofloxacin resistance. Multiresistance was more frequent among singleton isolates (61%) than clonal isolates (40%) of quinolone resistant Escherichia coli. Ciprofloxacin resistance was associated with certain specific clones, among them the globally distributed clonal Group A. However, there was no significant difference in the overall degree of clonality between quinolone sensitive and resistant isolates. Ciprofloxacin resistance was positively associated with phylogroup D and negatively associated with phylogroup B2. This correlation was not associated with clonal isolates. Conclusion This study supports earlier findings of association between ciprofloxacin resistance and resistance to other antibiotics. The prevalence of multiresistance in quinolone-resistant isolates that have not yet developed high-level ciprofloxacin resistance suggest that multiresistance arises early in the development of quinolone resistance. This is consistent with exposure to quinolones causing quinolone resistance by mutations and mobilization of multiresistance elements by induction of the SOS response. The spread of clones seems to be less important than previously reported in regard to emergence of quinolone resistance and multiresistance as both are associated primarily with singleton isolates. PMID:24941949
Green synthesis of silver nanoparticles from leaf extract of Mimusops elengi, Linn. for enhanced antibacterial activity against multi drug resistant clinical isolates.
Green synthesis of metallic silver nanoparticles has attracted nowadays and alternative to physical and chemical approaches. In the present study, silver nanoparticles (AgNPs) were synthesized from leaf extract of Mimusops elengi, L. at room temperature. Formation of stable AgNPs at 1mM concentrations of silver nitrate (AgNO3) typically gave spherical shape particles with diameter range from 55 to 83nm. The kinetic properties of particle formation were proportional to the effect of concentration of AgNO3 solution. In order to identify the compounds responsible for the bioreduction of Ag(+) ion and the stabilization of AgNPs produced, the functional group present in Mimusops elengi, L. leaf extract was investigated using FTIR. The formation of nanoparticle was confirmed using the surface plasmon resonance band shown in UV-vis spectrophotometer. The topography and morphology of the particles were determined using scanning electron microscopy. The crystalline nature of nanoparticles was confirmed from the XRD pattern. Furthermore these green synthesized AgNPs were found to show higher antimicrobial efficacy against multi drug resistant clinical isolates. PMID:23563291
Prakash, P; Gnanaprakasam, P; Emmanuel, R; Arokiyaraj, S; Saravanan, M
The evidence for clonal spreading of quinolone resistance with a particular clonal complex of Campylobacter jejuni.
Campylobacter is the most prevalent cause of bacterial gastroenteritis worldwide and it represents a significant public health risk of increasing severity due to its escalating resistance to clinically important quinolone and macrolide antibiotics. As a zoonotic pathogen Campylobacter is transmitted along the food chain and naturally cycles from environmental waters, feedstuff, animals and food to humans. We determined antibiotic resistance profiles, as well as multilocus sequence types and flaA-SVR types for 52 C. jejuni isolated in Slovenia from human, animal, raw and cured chicken meat and water samples. Twenty-eight different sequence types, arranged in ten clonal complexes, three new allele types and five new sequence types were identified, indicating the relatively high diversity in a small group of strains. The assignment of strains from different sources to the same clonal complexes indicates their transmission along the food supply chain. The most prevalent clonal complex was CC21, which was also the genetic group with 95% of quinolone-resistant strains. Based on the genetic relatedness of these quinolone-resistant strains identified by polymerase chain reaction with a mismatch amplification mutation assay and sequencing of the quinolone resistance-determining region of the gyrA gene, we conclude that the high resistance prevalence observed indicates the local clonal spread of quinolone resistance with CC21. PMID:24534165
Kova?, J; Cade×, N; LuÜicky, M; Nielsen, E M°ller; Ocepek, M; Raspor, P; Mo×ina, S Smole
Subtle Changes in Endochin-Like Quinolone Structure Alter the Site of Inhibition within the Cytochrome bc1 Complex of Plasmodium falciparum.
The cytochrome bc1 complex (cyt bc1) is the third component of the mitochondrial electron transport chain and is the target of several potent antimalarial compounds, including the naphthoquinone atovaquone (ATV) and the 4(1H)-quinolone ELQ-300. Mechanistically, cyt bc1 facilitates the transfer of electrons from ubiquinol to cytochrome c and contains both oxidative (Qo) and reductive (Qi) catalytic sites that are amenable to small-molecule inhibition. Although many antimalarial compounds, including ATV, effectively target the Qo site, it has been challenging to design selective Qi site inhibitors with the ability to circumvent clinical ATV resistance, and little is known about how chemical structure contributes to site selectivity within cyt bc1. Here, we used the proposed Qi site inhibitor ELQ-300 to generate a drug-resistant Plasmodium falciparum clone containing an I22L mutation at the Qi region of cyt b. Using this D1 clone and the Y268S Qo mutant strain, P. falciparum Tm90-C2B, we created a structure-activity map of Qi versus Qo site selectivity for a series of endochin-like 4(1H)-quinolones (ELQs). We found that Qi site inhibition was associated with compounds containing 6-position halogens or aryl 3-position side chains, while Qo site inhibition was favored by 5,7-dihalogen groups or 7-position substituents. In addition to identifying ELQ-300 as a preferential Qi site inhibitor, our data suggest that the 4(1H)-quinolone scaffold is compatible with binding to either site of cyt bc1 and that minor chemical changes can influence Qo or Qi site inhibition by the ELQs. PMID:25605352
Stickles, Allison M; de Almeida, Mariana Justino; Morrisey, Joanne M; Sheridan, Kayla A; Forquer, Isaac P; Nilsen, Aaron; Winter, Rolf W; Burrows, Jeremy N; Fidock, David A; Vaidya, Akhil B; Riscoe, Michael K
Synthesis, antiproliferative and antibacterial activity of new amides of salinomycin.
A series of 11 novel amides of salinomycin were synthesized for the first time. All the obtained compounds were found to show potent antiproliferative activity against human cancer cell lines including the drug-resistant cancer cells. Four new salinomycin derivatives revealed good antibacterial activity against clinical isolates of methicillin-resistant Staphylococcus epidermidis (MRSE). PMID:24631190
Antoszczak, Micha?; Maj, Ewa; Stefa?ska, Joanna; Wietrzyk, Joanna; Janczak, Jan; Brzezinski, Bogumil; Huczy?ski, Adam
The future challenges facing the development of new antimicrobial drugs
The emergence of resistance to antibacterial agents is a pressing concern for human health. New drugs to combat this problem are therefore in great demand, but as past experience indicates, the time for resistance to new drugs to develop is often short. Conventionally, antibacterial drugs have been developed on the basis of their ability to inhibit bacterial multiplication, and this
Yanmin Hu; Richard Bax; Clive Page; Anthony Coates
Plasmid-Mediated Quinolone Resistance; Interactions between Human, Animal, and Environmental Ecologies
Resistance to quinolones and fluoroquinolones is being increasingly reported among human but also veterinary isolates during the last two to three decades, very likely as a consequence of the large clinical usage of those antibiotics. Even if the principle mechanisms of resistance to quinolones are chromosome-encoded, due to modifications of molecular targets (DNA gyrase and topoisomerase IV), decreased outer-membrane permeability (porin defect), and overexpression of naturally occurring efflux, the emergence of plasmid-mediated quinolone resistance (PMQR) has been reported since 1998. Although these PMQR determinants confer low-level resistance to quinolones and/or fluoroquinolones, they are a favorable background for selection of additional chromosome-encoded quinolone resistance mechanisms. Different transferable mechanisms have been identified, corresponding to the production of Qnr proteins, of the aminoglycoside acetyltransferase AAC(6?)-Ib-cr, or of the QepA-type or OqxAB-type efflux pumps. Qnr proteins protect target enzymes (DNA gyrase and type IV topoisomerase) from quinolone inhibition. The AAC(6?)-Ib-cr determinant acetylates several fluoroquinolones, such as norfloxacin and ciprofloxacin. Finally, the QepA and OqxAB efflux pumps extrude fluoroquinolones from the bacterial cell. A series of studies have identified the environment to be a reservoir of PMQR genes, with farm animals and aquatic habitats being significantly involved. In addition, the origin of the qnr genes has been identified, corresponding to the waterborne species Shewanella sp. Altogether, the recent observations suggest that the aquatic environment might constitute the original source of PMQR genes, that would secondly spread among animal or human isolates. PMID:22347217
Poirel, Laurent; Cattoir, Vincent; Nordmann, Patrice
[Advance in studies on antibacterial effect of flavonoids].
As antibiotic drug resistance has become one of the most serious threats to global public health, there is a pressing need to look for new effective therapeutic drugs. Flavonoids are a large class of chemicals widely exist in plants, and have such effects as direct antibiotics, synergistic antibiotics and inhibition of bacterial activity. In this article, we made a summary for the advance in studies on the antibacterial effects of flavonoids and their mechanism. PMID:24494547
You, Ting-Huo; Liu, Fan; Wen, Lu; Zou, Yu-Xiao; Liao, Sen-Tai; Xiao, Geng-Sheng
Drug interactions with antiviral drugs.
Antiviral drug interactions are a particular problem among immuno-compromised patients because these patients are often receiving multiple different drugs, i.e. antiretroviral drugs and drugs effective against herpesvirus. The combination of zidovudine and other antiretroviral drugs with different adverse event profiles, such as didanosine, zalcitabine and lamivudine, appears to be well tolerated and no relevant pharmacokinetic interactions have been detected. The adverse effects of didanosine and zalcitabine (i.e. peripheral neuropathy and pancreatitis) should be taken into account when administering these drugs with other drugs with the same tolerability profile. Coadministration of zidovudine and ganciclovir should be avoided because of the high rate of haematological intolerance. In contrast, zidovudine and foscarnet have synergistic effect and no pharmacokinetic interaction has been detected. No major change in zidovudine pharmacokinetics was seen when the drug was combined with aciclovir, famciclovir or interferons. However, concomitant use of zidovudine and ribavirin is not advised. Although no pharmacokinetic interaction was documented when didanosine was first administered with intravenous ganciclovir, recent studies have shown that concentration of didanosine are increased by 50% or more when coadministered with intravenous or oral ganciclovir. The mechanism of this interaction has not been elucidated. Lack of pharmacokinetic interaction was demonstrated between foscarnet and didanosine or ganciclovir. Clinical trials have shown that zidovudine can be administered safely with paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, oxazepam or codeine. Inhibition of zidovudine glucuronidation has been demonstrated with fluconazole, atovaquone, valproic acid (valproate sodium), methadone, probenecid and inosine pranobex; however, the clinical consequences of this have not been fully investigated. No interaction has been demonstrated with didanosine per se but care should be taken of interaction with the high pH buffer included in the tablet formulation. Drugs that need an acidic pH for absorption (ketoconazole, itraconazole but not fluconazole, dapsone, pyrimethamine) or those that can be chelated by the ions of the buffer (quinolones and tetracyclines) should be administered 2 hours before or 6 hours after didanosine. Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid 'Maalox' results in a reduction of its absorption. Dapsone does not influence the disposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazole) causes an increase in lamivudine concentrations by 43%. Saquinavir, delavirdine and atevirdine appeared to be metabolised by cytochrome P450 and interactions with enzyme inducers or inhibitors could be anticipated. Some studies showed that interferons can reduce drug metabolism but only a few studies have evaluated the pathways involved. Further studies are required to better understand the clinical consequences of drug interactions with antiviral drugs. Drug-drug interactions should be considered in addition to individual drug clinical benefits and safety profiles. PMID:8743337
Taburet, A M; Singlas, E
HPTLC and antibacterial analysis of extracts of Cressa cretica Linn.
Plants used in traditional medicine are potential sources of new biologically active compounds many of them with antibacterial and antifungal activity. Plants can serve as a source of model compounds for synthetic or semi synthetic structure modification (Balandrin et al., 1993). Potential natural and synthetic substances with biocidal activity are considered candidates for developing new drugs for treatment of various chronic as well as infectious diseases. In the present investigation, HPTLC analysis is carried out with the various extracts of Cressa cretica L. to identify the number of phytoconstituents and their antibacterial activity is also tested. PMID:22557271
Suganthi, G; Sripathy, Shubashini K; Manian, K
HPTLC and antibacterial analysis of extracts of Cressa cretica Linn
Plants used in traditional medicine are potential sources of new biologically active compounds many of them with antibacterial and antifungal activity. Plants can serve as a source of model compounds for synthetic or semi synthetic structure modification (Balandrin et al., 1993). Potential natural and synthetic substances with biocidal activity are considered candidates for developing new drugs for treatment of various chronic as well as infectious diseases. In the present investigation, HPTLC analysis is carried out with the various extracts of Cressa cretica L. to identify the number of phytoconstituents and their antibacterial activity is also tested. PMID:22557271
Suganthi, G.; Sripathy, Shubashini K.; Manian, K.
An outpatient antibacterial stewardship intervention during the journey to JCI accreditation
Background Antibacterial overuse, misuse and resistance have become a major global threat. The Joint Commission International (JCI) accreditation standards include quality improvement and patient safety, which is exemplified by antimicrobial stewardship. There are currently few reports on interventions to improve the quality of outpatient antibacterial prescribing. Methods A before-after intervention study, aiming at antibacterial use in outpatients, was performed in a university-affiliated hospital with 2.8 million outpatient visits annually during the journey to JCI accreditation (March of 2012 - March of 2013). Comprehensive intervention measures included formulary adjustment, classification management, motivational, information technological, educational and organizational measures. A defined daily dose (DDD) methodology was applied. Pharmacoeconomic data and drug-related problems (DRPs) were statistically compared between the two phases. Results The variety of antibacterials available in outpatient pharmacy decreased from 38 to 16. The proportion of antibacterial prescriptions significantly decreased (12.7% versus 9.9%, P?0.01). The proportion of prescriptions containing the restricted antibacterials was 30.4% in the second phase, significantly lower than the value of 44.7% in the first phase (P?0.01). The overall proportion of oral versus all antibacterial prescriptions increased (94.0% to 100%, P?0.01) when measured as defined daily doses. Statistically significant increases in relative percentage of DDDs of oral antibacterials (i.e., DDDs of individual oral antibacterial divided by the sum of DDDs of all antibacterials) were observed with moxifloxacin, levofloxacin, cefuroxime axetil, ornidazole, clindamycin palmitate, cefaclor, amoxicillin and clarithromycin. Occurrence rate of DRPs decreased from 13.6% to 4.0% (P?0.01), with a larger decrease seen in surgical clinics (surgical: 19.5% versus 5.6%; internal medicine: 8.4% versus 2.8%, P?0.01). The total expenditure on antibacterials for outpatients decreased by 34.7% and the intervention program saved about 6 million Chinese Yuan Renminbi (CNY) annually. Conclusion The one-year intervention program on outpatient antibacterial use during the journey to JCI accreditation reduced the expenditure on antibacterials, improved the appropriateness of antibacterial prescriptions. Quality improvements need integrated multifaceted intervention measures and long-term adherence to the antibiotic stewardship. Approach of i.v. to oral antibacterial switch, classification management, and motivational measures may play the most efficient role in changing antibacterial prescription practices. PMID:24568120
Membrane active phenylalanine conjugated lipophilic norspermidine derivatives with selective antibacterial activity.
Natural and synthetic membrane active antibacterial agents offer hope as potential solutions to the problem of bacterial resistance as the membrane-active nature imparts low propensity for the development of resistance. In this report norspermidine based antibacterial molecules were developed that displayed excellent antibacterial activity against various wild-type bacteria (Gram-positive and Gram-negative) and drug-resistant bacteria (methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and ?-lactam-resistant Klebsiella pneumoniae). In a novel structure-activity relationship study it has been shown how incorporation of an aromatic amino acid drastically improves selective antibacterial activity. Additionally, the effect of stereochemistry on activity, toxicity, and plasma stability has also been studied. These rapidly bactericidal, membrane active antibacterial compounds do not trigger development of resistance in bacteria and hence bear immense potential as therapeutic agents to tackle multidrug resistant bacterial infections. PMID:25335118
Konai, Mohini M; Ghosh, Chandradhish; Yarlagadda, Venkateswarlu; Samaddar, Sandip; Haldar, Jayanta
Antibacterial activity of Cichorium intybus
Antibacterial activity of the water, ethanol and ethyl acetate extracts of Cichorium intybus was investigated. All the tested extracts showed antibacterial activity, the ethyl acetate extract being the most active. Water extract inhibits Agrobacterium radiobacter sp. tumefaciens, Erwinia carotovora, Pseudomonas fluorescens and P. aeruginosa.
J. Petrovic; A. Stanojkovic; Lj. Comic; S. Curcic
In vitro activities of five new quinolones against 88 genital and neonatal Haemophilus isolates.
In vitro activities of five new quinolones against 88 strains of Haemophilus influenzae and H. parainfluenzae isolated from genitourinary or neonatal infections were studied. All strains were susceptible, and MICs were similar to those for respiratory tract isolates. However, H. influenzae biotype IV appeared to be more susceptible to norfloxacin, enoxacin, and ciprofloxacin than the other biotypes were. PMID:3258143
Quentin, R; Koubaa, N; Cattier, B; Gavignet, M; Goudeau, A
Genetic Diversity and Quinolone Resistance in Campylobacter jejuni Isolates from Poultry in Senegal
We used the multilocus sequence typing (MLST) method to evaluate the genetic diversity of 46 Campylobacter jejuni isolates from chickens and to determine the link between quinolone resistance and sequence type (ST). There were a total of 16 ST genotypes, and the majority of them belonged to seven clonal complexes previously identified by using isolates from human disease. The ST-353 complex was the most common complex, whereas the ST-21, ST-42, ST-52, and ST-257 complexes were less well represented. The resistance phenotype varied for each ST, and the Thr-86-Ile substitution in the GyrA protein was the predominant mechanism of resistance to quinolone. Nine of the 14 isolates having the Thr-86-Ile substitution belonged to the ST-353 complex. MLST showed that the emergence of quinolone resistance is not related to the diffusion of a unique clone and that there is no link between ST genotype and quinolone resistance. Based on silent mutations, different variants of the gyrA gene were shown to exist for the same ST. These data provide useful information for understanding the epidemiology of C. jejuni in Senegal. PMID:16672471
Kinana, Alfred Dieudonnķ; Cardinale, Eric; Tall, Fatou; Bahsoun, Ibrahim; Sire, Jean-Marie; Garin, Benoit; Breurec, Sebastien; Boye, Cheikh Saad-Bouh; Perrier-Gros-Claude, Jean-David
Identification for mar mutants among quinolone-resistant clinical isolates of Escherichia coli.
Quinolone-resistant clinical Escherichia coli isolates were examined for mutations in the marRAB operon of the multiple antibiotic resistance (mar) locus. Among 23 strains evaluated, 8 were chosen for further study: 3 that showed relatively high levels of uninduced, i.e., constitutive, expression of the operon and 5 with variable responses to induction by salicylate or tetracyclines. The marR genes, specifying the repressor of the operon, cloned from the three strains constitutively expressing the operon did not reduce the level of expression of beta-galactosidase from a marO::lacZ transcriptional fusion and were therefore mutant; however, marR genes cloned from the five other clinical strains repressed LacZ expression and were wild type. All three mutant marR genes contained more than one mutation: a deletion and a point mutation. Inactivation of the mar locus in the three known marR mutant strains with a kanamycin resistance cassette introduced by homologous recombination reduced resistance to quinolones and multiple antibiotics. These findings indicate that mar operon mutations exist in quinolone-resistant clinical E. coli isolates and contribute to quinolone and multidrug resistance. PMID:8807064
Maneewannakul, K; Levy, S B
Development of quinolone-resistant Campylobacter fetus bacteremia in human immunodeficiency virus-infected patients.
Campylobacter fetus subspecies fetus has been recognized as a cause of systemic illness in immunocompromised hosts, including relapsing bacteremia in human immunodeficiency virus (HIV)-infected patients. Acquired resistance to quinolone therapy, while reported for a variety of bacteria, including Campylobacter jejuni, has not been previously documented for C. fetus. Two cases of quinolone-resistant C. fetus bacteremia were detected in HIV-infected patients. Cloning and nucleotide sequencing of the C. fetus gyrA gene in the 2 resistant isolates demonstrated a G-to-T change that led to an Asp-to-Tyr amino acid substitution at a critical residue frequently associated with quinolone resistance. In addition, comparison of the pre- and posttreatment isolates from 1 patient documented outer membrane protein changes temporally linked with the development of resistance. Relapsing C. fetus infections in quinolone-treated HIV-infected patients may be associated with the acquisition of resistance to these agents, and this resistance may be multifactorial. PMID:9534967
Meier, P A; Dooley, D P; Jorgensen, J H; Sanders, C C; Huang, W M; Patterson, J E
Interspecies Recombination Occurs Frequently in Quinolone Resistance-Determining Regions of Clinical Isolates of Streptococcus pyogenes?
Fluoroquinolone resistance in Streptococcus pyogenes has been reported only anecdotally, but a recent Belgian surveillance study found a rate of nonsusceptibility of 5.4%. From an analysis of these isolates, we show that interspecies horizontal gene transfer within the parC quinolone resistance-determining region is a frequent phenomenon that might contribute to fluoroquinolone resistance. PMID:18765693
Duesberg, Christoph B.; Malhotra-Kumar, Surbhi; Goossens, Herman; McGee, Lesley; Klugman, Keith P.; Welte, Tobias; Pletz, Mathias W. R.
Use of quinolones in treatment of prostatitis and lower urinary tract infections
The newer quinolones, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, norfloxacin, ofloxacin and pefloxacin are highly effective antimicrobial agents against the majority of bacteria responsible for urinary tract infections and bacterial prostatitis. The pharmacokinetic properties of these agents after oral administration result in high concentrations in human urine, as well as in prostatic fluid and prostatic tissue. Ciprofloxacin, enoxacin and lomefloxacin produce the
V. T. Andriole
Detection of Quinolone-Resistance Mutations In Salmonella Spp. Strains of Epidemic and Poultry Origin
Mutations into codons Aspartate-87 (62%) and Serine-83 (38%) in QRDR of gyrA were identified in 105 Salmonella strains resistant to nalidixic acid (94 epidemic and 11 of poultry origin). The results show a high incidence of mutations associated to quinolone resistance but suggest association with others mechanisms of resistance. PMID:24031623
de Souza, Roberta Barreiros; Magnani, Marciane; Ferrari, Rafaela Gomes; Kottwitz, Luciana Bill Mikito; Sartori, Daniele; Tognim, Maria Cristina Bronharo; de Oliveira, Tereza Cristina R. M.
Microbial screening for quinolones residues in cow milk by bio-optical method.
The use of antibiotics on lactating cows should be monitored for the possible risk of milk contamination with residues. Accordingly, Maximum Residue Levels (MRLs) are established by the European Commission to guarantee consumers safety. As pointed out by Dec 2002/657/EC, screening is the first step in the strategy for antibiotic residue control, thus playing a key role in the whole control procedure. However, current routine screening methods applied in milk chain still fail to detect residues of quinolones at concentrations of interest. This paper reports the findings of a new bio-optical method for the screening of quinolones residues in bovine milk, based on E. coli ATCC 11303 growth inhibition. The effect of blank and spiked cow milk samples (aliquots equivalents to 0.8%, v/v) is evaluated in Mueller Hinton Broth (MHb) and MHb enriched with MgSO4 2% (MHb-Mg) inoculated with the test strain at the concentration of 10(4)CFU/mL. The presence of quinolones inhibits the cellular growth in MHb, while this effect is neutralized in MHb-Mg allowing both detection and presumptive identification of quinolones. Growth of the test strain is monitored at 37░C in a Bioscreen C automated system, and Optical Density (OD) at 600nm is recorded every 10min after shaking for 10s. Growth curves (OD vs. time) of E. coli ATCC 11303 are assessed in milk samples, with and without quinolones, and their differences in terms of ?OD (?OD600nm=ODMHb-Mg-ODMHb) are calculated. The presence of quinolones is detected by the cellular growth inhibition (OD vs time, none increase in the value OD) and presumptively identified through the increase of the slope of ?OD600nm curve (?OD vs. time), after about 3h of incubation. The detection limit for ciprofloxacin and enrofloxacin is at the level of MRL, for marbofloxacin is at 2-fold the MRL whereas for danofloxacin is at 4-fold the MRL. Although the sensitivity of the method could be further improved and the procedure automated, it is a promising step forward to integrate screening assays into the control process and, in particular, to fill in the gap for quinolones; moreover, these technological developments contribute to the One Health perspective through the monitoring of safe and correct use of veterinary antibiotics. PMID:25555518
Appicciafuoco, Brunella; Dragone, Roberto; Frazzoli, Chiara; Bolzoni, Giuseppe; Mantovani, Alberto; Ferrini, Anna Maria
Antibacterial polyelectrolyte-coated Mg alloys for biomedical applications
NASA Astrophysics Data System (ADS)
This study deals with two biomedical subjects: corrosion rates of polyelectrolyte-coated magnesium (Mg) alloys, mainly used for biomedical purposes, and antibacterial properties of these alloys. Thin sheets of Mg alloys were coated with cationic polyelectrolyte chitosan (CHI) and anionic polyelectrolyte carboxymethyl cellulose (CMC) using a layer-by-layer coating method and then embedded with antibacterial agents under vacuum. Electrochemical impedance spectroscopy was employed to analyze these samples in order to detect their corrosion properties at different conditions. In the electrochemical analysis section, a corrosion rate of 72 mille inches per year was found in a salt solution for the sample coated with a 12 phosphonic acid self-assembled monolayer and 9 CHI/CMC multilayers. In the antibacterial tests, gentamicin was used to investigate the effects of the drug embedded with the coated surfaces against the Escherichia coli (E. coli) bacteria. Antibacterial studies were tested using the disk diffusion method. Based on the standard diameter of the zone of inhibition chart, the antibacterial diffusion from the surface strongly inhibited bacterial growth in the regions. The largest recorded diameter of the zone of inhibition was 50 mm for the pre-UV treated and gentamicin-loaded sample, which is more than three times the standard diameter.
Seraz, Md. S.; Asmatulu, R.; Chen, Z.; Ceylan, M.; Mahapatro, A.; Yang, S. Y.
Influence of CO(2) incubation on quinolone activity against Streptococcus pneumoniae and Haemophilus influenzae.
Quinolone activity can be influenced by the pH change that occurs during CO(2) incubation when testing capnophilic organisms such as Streptococcus pneumoniae and Haemophilus influenzae. This study compares the activity of ciprofloxacin, clinafloxacin, enrofloxacin, fleroxacin, grepafloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, sparfloxacin, trovafloxacin, and the glycopeptide vancomycin, under ambient air and supplemental CO(2) incubation conditions. Etest (AB BIODISK, Solna, Sweden) was used to determine the MIC values of 30 S. pneumoniae strains including S. pneumoniae ATCC 49619 and 6030; and 29 H. influenzae strains including H. influenzae ATCC 49247 and 49766, incubated with and without 5% CO(2.) Reference broth microdilution and agar dilution tests were performed under similar conditions. Results determined that MIC values of all quinolones agreed (> or = 95%) within +/- one log(2) dilution for the three test methods tested under identical incubation conditions. Quinolone MICs for S. pneumoniae were minimally influenced by CO(2,) while MIC values for H. influenzae ranged from 0.5 to two log(2) dilutions higher when incubated in the CO(2) environment. The differences in quinolone activity against H. influenzae may be due to a combination of pH effects and enhanced growth in the CO(2) test conditions. Quality control and interpretative criteria, especially for H. influenzae and quinolones published by the National Committee for Clinical Laboratory Standards, may not be fully applicable to results obtained under CO(2) incubation. This may generate potential therapeutic interpretive dilemmas in the susceptibility testing of H. influenzae, where clinical isolates require CO(2) to sustain acceptable growth. PMID:11821174
Bolmstrom, A; Karlsson, A
Decay mechanisms of protonated 4-quinolone antibiotics after electrospray ionization and ion activation.
This study presents a detailed experimental investigation of charge isomers of protonated 4-quinolone antibiotics molecules formed during electrospray ionization (ESI) with proposed dissociation mechanisms after collisional activation. Piperazinyl quinolones have been previously shown to exhibit erratic behavior during tandem MS analyses of biological samples, which originated from varying ratios of two isomeric variants formed during ESI. Here, a combination of ESI-collision-induced dissociation (CID), differential ion mobility spectrometry (DMS), high resolution MS, and density functional theory (DFT) was used to investigate the underlying mechanisms of isomer formation and their individual dissociation behaviors. The study focused on ciprofloxacin; major findings were confirmed using structurally related 4-quinolones. DFT calculations showed a reversal of basicity for piperazinyl quinolones between liquid and gas phase. We provide an experimental comparison and theoretical treatment of factors influencing the formation ratio of the charge isomers during ESI, including solvent pH, protic/aprotic nature of solvent, and structural effects such as pK a and proton affinity. The actual dissociation mechanisms of the isomers of the protonated molecules were studied by separating the individual isomers via DMS-MS, which allowed type-specific CID spectra to be recorded. Both primary CID reactions of the two charge isomers originated from the same carboxyl group by charge-remote (CO(2) loss) and charge-mediated (H(2)O loss) fragmentation of the piperazinyl quinolones, depending on whether the proton resides on the more basic keto or the piperazinyl group, followed by a number of secondary dissociation reactions. The proposed mechanisms were supported by calculated energies of precursors, transition states, and products for competing pathways. PMID:25201456
Kova?evi?, Borislav; Schorr, Pascal; Qi, Yulin; Volmer, Dietrich A
Antibacterial efficacy of acridine derivatives conjugated with gold nanoparticles.
Adsorption of acridine derivatives viz. 9-aminoacridine hydrochloride hydrate (9AA-HCl), acridine yellow (AY), acridine orange (AO), and proflavine (Pro) on citrate stabilized gold nanoparticle surface were studied using different analytical techniques like UV-vis absorption spectroscopy, Fourier transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM). The amine moiety of acridine derivative binds strongly to the gold nanoparticles as confirmed by spectroscopic studies. The plasmon band observed for the wine red colloidal gold at 525 nm in the UV-vis spectrum is characteristic of gold nanoparticles. However, with the addition of acridine derivatives the intensity of the absorption band at 525 nm decreases and a new peak emerges at red-end region - a signature of formation of gold-drug complex. The TEM images show the average size of citrate stabilized gold nanoparticles as 15-20 nm, which becomes larger in the presence of various drugs due to aggregation. From the thermogravimetric analyses (TGA) we have measured the number of drug molecules attached per gold nanoparticle (AuNP). These gold nanoparticles are very important as drug delivery vehicles and for clinical applications it is necessary to understand their activity in vivo. The antibacterial efficacy of drugs coated gold nanoparticles were studied against various strains of Gram positive and Gram negative bacteria. Among the four drugs, 9AA-HCl and AO showed antibacterial activity and for both of them the AuNP conjugated drug showed better antibacterial efficacy than the bare drug. Because of the high penetrating power and large surface area of Au(0), a single gold nanoparticle can adsorb multiple drug molecules, hence this total entity acts as a single group against the bacteria. PMID:25087507
Mitra, Piyali; Chakraborty, Prabal Kumar; Saha, Partha; Ray, Pulak; Basu, Samita
Multi-residue method for the detection of veterinary drugs in distillers grains by liquid chromatography-Orbitrap high resolution mass spectrometry.
Distillers Grain (DG) is an important by-product of ethanol production. The ethanol production process uses only the starch portion of the plant and all the remaining nutrients, protein, fat, minerals, and vitamins remain in DGs, a valuable feed material for livestock. The use of antimicrobial drugs is helpful to limit harmful bacterial growth during the early part of the fermentation process. This can lead to the possible presence of contaminants in the by-products that are used in the food and feed industries, resulting in a major concern for the development of bacterial resistance in both humans and animals. To facilitate the detection of antimicrobial and other commonly used veterinary drugs in DGs, a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method was developed targeting a wide range of 12 chemical classes of anti-bacterial substances and drugs, such as ionophore and non-ionophore authorized coccidiostats, banned coccidiostats, macrolides, tetracyclines, nitroimidazoles, amphenicols, quinolones, sulphonamides, tranquilizers, non-steroidal anti-inflammatory drugs and benzimidazoles. Following a simple and fast extraction step with a mixture of organic solvents, the extract was directly injected into the LC coupled to an Orbitrap mass analyzer. The identification of residues is based on accurate mass measurement. The high mass resolution of 50,000 full width at half maximum (FWHM) and corresponding narrow mass windows permitted a very selective and sensitive detection of the analytes in such a complex matrix. A single-laboratory validation procedure was carried out evaluating selectivity, sensitivity, linearity, precision and accuracy. The method showed satisfactory analytical performance for precision and trueness, and allowed the determination of the compounds at low concentration. The proposed multi-method demonstrated that liquid chromatography coupled to an Orbitrap mass spectrometer is a promising analytical technique, suitable for official residue control of a variety of veterinary drugs in DGs supporting feed safety policies. PMID:24239439
Kaklamanos, George; Vincent, Ursula; von Holst, Christoph
Development of in vitro Antimicrobial Resistance in Bacteria Exposed to Residue Level Exposures of Antimicrobial Drugs, Pesticides and Veterinary Drugs
Ten ppb or less of antibacterial drugs, pesticides and veterinary drugs could increase antibacterial resistance in bacteria. The minimum inhibitory concentration (MIC) was the indicator of resistance and Staphylococcus aureus ATCC 9144 the indicator organism. Seventeen compounds used in human, veterinary medicine, crop production, and found in the environment, were studied singly, and as combinations. Single compounds decreased MIC values
David K. Kleiner; Stanley E. Katz; Paula-Marie L. Ward
Structure of PqsD, a Pseudomonas Quinolone Signal Biosynthetic Enzyme, in Complex with Anthranilateå
Pseudomonas quinolone signal (PQS), 2-heptyl-3-hydroxy-4-quinolone, is an intercellular alkyl quinolone signaling molecule produced by the opportunistic pathogen Pseudomonas aeruginosa. Alkyl quinolone signaling is an atypical system that, in P. aeruginosa, controls the expression of numerous virulence factors. PQS is synthesized from the tryptophan pathway intermediate, anthranilate, which is either derived from the kynurenine pathway or from an alkyl quinolone specific anthranilate synthase encoded by phnAB. Anthranilate is converted to PQS by the enzymes encoded by the pqsABCDE operon and pqsH. PqsA forms an activated anthraniloyl-CoA thioester that shuttles anthranilate to the PqsD active site where it is transferred to Cys112 of PqsD. In the only biochemically characterized reaction, a condensation then occurs between anthraniloyl-PqsD and malonyl-CoA or malonyl-ACP, a second PqsD substrate, forming 2,4-dihydroxyquinoline (DHQ). The role PqsD plays in the biosynthesis of other alkyl quinolones, such as PQS, is unclear though it has been reported to be required for their production. No evidence however, exists that DHQ is a PQS precursor. Here we present a structural and biophysical characterization of PqsD that includes several crystal structures of the enzyme including that of the PqsD-anthranilate covalent intermediate and the inactive Cys112Ala active site mutant in complex with anthranilate. The structure reveals that PqsD is structurally similar to the FabH and chalcone synthase families of fatty acid and polyketide synthases. The crystallographic asymmetric unit contains a PqsD dimer. The PqsD monomer is composed of two nearly identical ~170 residue ????? domains. The structures show anthranilate-liganded Cys112 is positioned deep in the protein interior at the bottom of a ~15 ┼ long channel while a second anthraniloyl-CoA molecule is waiting in the cleft leading to the protein surface. Cys112, His257, and Asn287 form the FabH-like catalytic triad of PqsD. The C112A mutant is inactive although it still reversibly binds anthraniloyl-CoA. The covalent complex between anthranilate and Cys112 clearly illuminates the orientation of key elements of the PqsD catalytic machinery and represents a snapshot of a key point in the catalytic cycle. PMID:19694421
Bera, Asim K.; Atanasova, Vesna; Robinson, Howard; Eisenstein, Edward; Coleman, James P.; Pesci, Everett C.; Parsons, James F.
Controlled release of antibiotics encapsulated in the electrospinning polylactide nanofibrous scaffold and their antibacterial and biocompatible properties
NASA Astrophysics Data System (ADS)
In this research, the drug loaded polylactide nanofibers are fabricated by electrospinning. Morphology, microstructure and mechanical properties are characterized. Properties and mechanism of the controlled release of the nanofibers are investigated. The results show that the drug loaded polylactide nanofibers do not show dispersed phase, and there is a good compatibility between polylactide and drugs. FTIR spectra show that drugs are encapsulated inside the polylactide nanofibers, and drugs do not break the structure of polylcatide. Flexibility of drug loaded polylactide scaffolds is higher than that of the pure polylactide nanofibers. Release rate of the drug loaded nanofibers is significantly slower than that of the drug powder. Release rate increases with the increase of the drugsÆ concentration. The research mechanism suggests a typical diffusion-controlled release of the three loaded drugs. Antibacterial and cell culture show that drug loaded nanofibers possess effective antibacterial activity and biocompatible properties.
Wang, Shu-Dong; Zhang, Sheng-Zhong; Liu, Hua; Zhang, You-Zhu
Comparative Analysis of Quinolone Resistance in Clinical Isolates of Klebsiella pneumoniae and Escherichia coli from Chinese Children and Adults
The objective of this study was to compare quinolone resistance and gyrA mutations in clinical isolates of Klebsiella pneumoniae and Escherichia coli from Chinese adults who used quinolone in the preceding month and children without any known history of quinolone administration. The antimicrobial susceptibilities of 61 isolates from children and 79 isolates from adults were determined. The mutations in the quinolone resistance-determining regions in gyrA gene were detected by PCR and DNA sequencing. Fluoroquinolone resistance and types of gyrA mutations in isolates from children and adults were compared and statistically analyzed. No significant differences were detected in the resistance rates of ciprofloxacin and levofloxacin between children and adults among isolates of the two species (all P > 0.05). The double mutation Ser83?Leu + Asp87?Asn in the ciprofloxacin-resistant isolates occurred in 73.7% isolates from the children and 67.9% from the adults, respectively (P = 0.5444). Children with no known history of quinolone administration were found to carry fluoroquinolone-resistant Enterobacteriaceae isolates. The occurrence of ciprofloxacin resistance and the major types of gyrA mutations in the isolates from the children were similar to those from adults. The results indicate that precautions should be taken on environmental issues resulting from widespread transmission of quinolone resistance. PMID:25756041
Huang, Ying; Ogutu, James O.; Gu, Jiarui; Ding, Fengshu; You, Yuhong; Huo, Yan; Zhao, Hong; Li, Wenjing; Zhang, Zhiwei; Zhang, Wenli; Chen, Xiaobei; Fu, Yingmei; Zhang, Fengmin
Comparative Analysis of Quinolone Resistance in Clinical Isolates of Klebsiella pneumoniae and Escherichia coli from Chinese Children and Adults.
The objective of this study was to compare quinolone resistance and gyrA mutations in clinical isolates of Klebsiella pneumoniae and Escherichia coli from Chinese adults who used quinolone in the preceding month and children without any known history of quinolone administration. The antimicrobial susceptibilities of 61 isolates from children and 79 isolates from adults were determined. The mutations in the quinolone resistance-determining regions in gyrA gene were detected by PCR and DNA sequencing. Fluoroquinolone resistance and types of gyrA mutations in isolates from children and adults were compared and statistically analyzed. No significant differences were detected in the resistance rates of ciprofloxacin and levofloxacin between children and adults among isolates of the two species (all P > 0.05). The double mutation Ser83?Leu + Asp87?Asn in the ciprofloxacin-resistant isolates occurred in 73.7% isolates from the children and 67.9% from the adults, respectively (P = 0.5444). Children with no known history of quinolone administration were found to carry fluoroquinolone-resistant Enterobacteriaceae isolates. The occurrence of ciprofloxacin resistance and the major types of gyrA mutations in the isolates from the children were similar to those from adults. The results indicate that precautions should be taken on environmental issues resulting from widespread transmission of quinolone resistance. PMID:25756041
Huang, Ying; Ogutu, James O; Gu, Jiarui; Ding, Fengshu; You, Yuhong; Huo, Yan; Zhao, Hong; Li, Wenjing; Zhang, Zhiwei; Zhang, Wenli; Chen, Xiaobei; Fu, Yingmei; Zhang, Fengmin
Molecular epidemiological survey on quinolone resistance genotype and phenotype of Escherichia coli in septicemic broilers in Hebei, China.
In this study, the quinolone-resistant determining region (QRDR) of gyrA of Escherichia coli and plasmid-mediated quinolone resistance (PMQR) genes, qnr(qnrA, qnrB, and qnrS), and aac(6?')-Ib-cr were detected, sequenced, and analyzed. In addition, antimicrobial susceptibility tests (using the Kirby-Bauer disc diffusion method) were performed for all 111 E. coli isolates from septicemic broilers in Hebei, China. The results show that the resistance rates were as follows: ofloxacin 99.10%, ciprofloxacin 93.69%, levofloxacin 91.89%, norfloxacin 90.09%, and gatifloxacin 76.58%. Of the PMQR genes examined, aac(6?')-Ib-cr (36.04%) was the most frequently identified gene in all isolates, followed by qnrS (8.11%), qnrB (0.90%), and qnrA (0%). Of the QRDR examined in the 40 phenotypic quinolone-resistant isolates, compared with the gyrA(+) gene of E. coli K-12, 4 amino acid exchanges were found, namely Ser-83?Asp, Asp-87?Asn, Asp-87?Tyr, and Asp-87?Ala, and all 40 isolates had 1 or 2 exchanges in QRDR. It was concluded that quinolone-resistance in E. coli remains a serious problem in Hebei, China. Therefore, there is considerable local surveillance of quinolone resistance. Plasmid-mediated quinolone resistance of the qnr type remains rare in Hebei, China, and mutation in QRDR may be the main problem. PMID:24570454
Xie, Rong; Huo, Shuying; Li, Yurong; Chen, Ligong; Zhang, Feiyan; Wu, Xianjun
High-level quinolone resistance in clinical isolates of Campylobacter jejuni.
During a recent clinical trial of ciprofloxacin in the therapy of acute diarrhea, two subjects infected with Campylobacter jejuni who received ciprofloxacin failed microbiologically and one also failed clinically. Although both pretreatment isolates were susceptible to ciprofloxacin, the posttreatment isolates were resistant to ciprofloxacin (MIC = 32 micrograms/ml) and to other quinolones. The posttreatment isolates remained susceptible to nonquinolone antimicrobials. DNA gyrase holoenzyme was isolated from one of the resistant posttreatment isolates and was 8- to 16-fold less sensitive to inhibition by ciprofloxacin than was the gyrase from the paired pretreatment susceptible isolate. Ciprofloxacin accumulation was diminished in the two resistant posttreatment isolates. These results show that mutation in C. jejuni can occur in vivo and is associated with clinically significant resistance to the newer quinolones. PMID:1313069
Segreti, J; Gootz, T D; Goodman, L J; Parkhurst, G W; Quinn, J P; Martin, B A; Trenholme, G M
Microbial response to antibacterial treatment in marine microcosms
In a previous study of sediments near three salmon open-water net-cage farms in Puget Sound, Washington we determined over a 5-month period the number of cultivable bacteria and the percentage of cultivable bacteria that were resistant to oxytetracycline (OTC), Romet« 30 (drug consisting of sulfadimethioxine and ormetoprim), or amoxycillin. These antibacterials are routinely used for the treatment of diseased salmon.
Russell P. Herwig; James P. Gray
In Vitro Activities of the Newer Quinolones Garenoxacin, Gatifloxacin, and Gemifloxacin against Human Mycoplasmas
The activities of garenoxacin, gatifloxacin, and gemifloxacin were compared with those of four fluoroquino- lones against human mycoplasmas and ureaplasmas, including fluoroquinolone-resistant genetically charac- terized strains. Garenoxacin exhibited the highest activity, followed by gemifloxacin, moxifloxacin, and gati- floxacin. The minimal bactericidal activities of these three compounds were lower than those of the four fluoroquinolones. Garenoxacin, a des-fluoro(6)-quinolone, and gemifloxacin and
S. Pereyre; H. Renaudin; C. Bebear
Two Distinct Pathways Supply Anthranilate as a Precursor of the Pseudomonas Quinolone Signal?
Pseudomonas aeruginosa is an opportunistic pathogen that causes serious infections in immunocompromised patients and those with cystic fibrosis (CF). This gram-negative bacterium uses multiple cell-to-cell signals to control numerous cellular functions and virulence. One of these signals is 2-heptyl-3-hydroxy-4-quinolone, which is referred to as the Pseudomonas quinolone signal (PQS). This signal functions as a coinducer for a transcriptional regulator (PqsR) to positively control multiple virulence genes and its own synthesis. PQS production is required for virulence in multiple models of infection, and it has been shown to be produced in the lungs of CF patients infected by P. aeruginosa. One of the precursor compounds from which PQS is synthesized is the metabolite anthranilate. This compound can be derived from the conversion of chorismate to anthranilate by an anthranilate synthase or through the degradation of tryptophan via the anthranilate branch of the kynurenine pathway. In this study, we present data which help to define the kynurenine pathway in P. aeruginosa and show that the kynurenine pathway serves as a critical source of anthranilate for PQS synthesis. We also show that the kyn pathway genes are induced during growth with tryptophan and that they are autoregulated by kynurenine. This study provides solid foundations for the understanding of how P. aeruginosa produces the anthranilate that serves as a precursor to PQS and other 4-quinolones. PMID:17337571
Farrow, John M.; Pesci, Everett C.
Characterization of ESBLs and associated quinolone resistance in Escherichia coli and Klebsiella pneumoniae isolates from an urban wastewater treatment plant in Algeria.
The aim of the study was the characterization of extended spectrum beta-lactamases (ESBLs) and quinolone resistance in cefotaxime-resistant coliform isolates from a wastewater treatment plant (WWTP). ESBLs were detected in 19 out of 24 isolates (79%) from raw water and in 21 out of 24 isolates (87.5%) from treated water, identified as Klebsiella pneumoniae and Escherichia coli. Molecular characterization of ESBLs and quinolone resistance showed allele profiles CTX-M-15 (3), CTX-M-3 (5), CTX-M-15+qnrB1 (1), CTX-M-3+qnrB1 (1), CTX-M-15+aac-(6')-Ib-cr (4), and CTX-M-15+qnrB1+aac-(6')-Ib-cr (7). A double mutation S83L and D87N (GyrA) and a single mutation S80I (ParC) were detected in ciprofloxacin-resistant E. coli isolates. In K. pneumoniae, mutations S83I (GyrA)+S80I (ParC) or single S80I mutation were detected in ciprofloxacin-resistant isolates, and no mutation was observed in ciprofloxacin-susceptible isolates. bla(CTX-M), qnrB1, and aac-(6')-Ib-cr were found, respectively, in these genetic environments: ISEcp1-bla(CTX-M)-orf477, orf1005-orf1-qnrB1, and Tn1721-IS26-aac-(6')-Ib-cr-bla(OXA-1)-catB4. bla(CTX-M-15) was located on IncF plasmid in E. coli and bla(CTX-M-3) on IncL/M plasmid in both species (E. coli and K. pneumoniae). E. coli isolates were affiliated to the phylogroups/MLST: D/ST405 (CC405), A/ST10 (CC10), A/ST617 (CC10), and B1/ST1431. K. pneumoniae isolates belonged to phylogroup KpI and to sequence types ST15, ST17, ST36, ST48, ST54, and ST147. The study showed a multi-drug resistance at the inflow and outflow of the WWTP, with ESBL production, plasmid-mediated quinolones resistance, and mutations in topoisomerases. The findings highlight the similarity of antibiotic resistance mechanisms in the clinical setting and the environment, and the role of the latter as a source of dissemination of resistance genes. PMID:23952363
Alouache, Souhila; Estepa, Vanesa; Messai, Yamina; Ruiz, Elena; Torres, Carmen; Bakour, Rabah
Evaluation of the Antibacterial Activity of Patchouli Oil
In the present study, the antimicrobial tests of patchouli oil were studied by using molecular docking technology and antimicrobial test in vitro. Five biological macromolecule enzymes, required by the bacteria in the process of biosynthesis were selected as target molecules. Five antibiotics benzylpenicillin, sulfadiazine, trimethoprim, rifampicin and ciprofloxacin, which are generally acknowledged as antibacterial drugs, were selected as reference compounds. The 3 three-dimensional (3D) structures of the 5 reference compounds and 26 compounds from patchouli oil were established by using surflex-dock software (8.1). And the 3D structures of five biological macromolecule enzymes derived from Protein Data Bank (PDB). Molecular docking was carried out between the 31 chemical compounds (ligands) and the 5 enzymes (receptors) by using surflex-dock function. Furthermore, the antibacterial effects of 31 chemical compounds were investigated by the scoring function after molecular docking was completed. By comparing the scoring result of 26 compounds in patchouli oil with 5 compared components, we inferred antibacterial activity in about 26 compounds in patchouli oil. On the other hand, six frequently-used pathogenic bacteria were selected for antimicrobial test in vitro, patchouli oil and its two major compounds: (-)-patchouli alcohol and pogostone, which their contents exceeded 60% in patchouli oil samples, were selected antibacterial agents. Minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) were also determined. Molecular docking technology and antimicrobial test in vitro proved that patchouli oil had strong antimicrobial effects. Particularly, pogostone and (-)-patchouli alcohol have potent antimicrobial activity. PMID:24250637
Yang, Xian; Zhang, Xue; Yang, Shui-Ping; Liu, Wei-Qi
Protein Interactions in Genome Maintenance as Novel Antibacterial Targets
Antibacterial compounds typically act by directly inhibiting essential bacterial enzyme activities. Although this general mechanism of action has fueled traditional antibiotic discovery efforts for decades, new antibiotic development has not kept pace with the emergence of drug resistant bacterial strains. These limitations have severely restricted the therapeutic tools available for treating bacterial infections. Here we test an alternative antibacterial lead-compound identification strategy in which essential protein-protein interactions are targeted rather than enzymatic activities. Bacterial single-stranded DNA-binding proteins (SSBs) form conserved protein interaction ōhubsö that are essential for recruiting many DNA replication, recombination, and repair proteins to SSB/DNA nucleoprotein substrates. Three small molecules that block SSB/protein interactions are shown to have antibacterial activity against diverse bacterial species. Consistent with a model in which the compounds target multiple SSB/protein interactions, treatment of Bacillus subtilis cultures with the compounds leads to rapid inhibition of DNA replication and recombination, and ultimately to cell death. The compounds also have unanticipated effects on protein synthesis that could be due to a previously unknown role for SSB/protein interactions in translation or to off-target effects. Our results highlight the potential of targeting protein-protein interactions, particularly those that mediate genome maintenance, as a powerful approach for identifying new antibacterial compounds. PMID:23536821
Walsh, Brian W.; Shapiro, Walker; Simmons, Lyle A.; Keck, James L.
Antibacterial efficacy of Rumex nepalensis Spreng. roots.
The antibacterial property of Rumex nepalensis Spreng. was evaluated against some strains of bacteria. The methanol extract of the roots (tested at 200-1000 micro g/disc) showed significant concentration-dependent antibacterial activity. PMID:12748999
Ghosh, Lopamudra; Gayen, Jiaur Rahaman; Sinha, Sanghamitra; Pal, Sanchayita; Pal, M; Saha, B P
Interactions of Fluoroquinolone Antibacterial Agents with Aqueous
, including E. coli and common Aeromonas and Pseudomonas strains (14). Continuous exposure of bacterialInteractions of Fluoroquinolone Antibacterial Agents with Aqueous Chlorine: Reaction Kinetics extensively investigated to elucidate the behavior of fluoroquinolone antibacterial agents during water
Huang, Ching-Hua
Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099).
AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials. PMID:24959892
Basarab, Gregory S; Hill, Pamela J; Garner, C Edwin; Hull, Ken; Green, Oluyinka; Sherer, Brian A; Dangel, P Brian; Manchester, John I; Bist, Shanta; Hauck, Sheila; Zhou, Fei; Uria-Nickelsen, Maria; Illingworth, Ruth; Alm, Richard; Rooney, Mike; Eakin, Ann E
Antibacterial activities in various tissues of the horse mussel, Modiolus modiolus.
A search for antibacterial activity in different organs/tissues of the horse mussel, Modiolus modiolus, was conducted. Dried samples were extracted with 60% (v/v) acetonitrile, containing 0.1% (v/v) trifluoroacetic acid. Due to high salt content, two liquid phases were obtained; an acetonitrile-rich phase (ACN extract) and an aqueous phase. The aqueous phase was further subjected to solid phase extraction (SPE). Eluates from SPE and ACN extracts were tested for antibacterial, lysozyme, and toxic activity. Antibacterial activity was demonstrated in extracts from several tissues, including plasma, haemocytes, labial palps, byssus, mantle, and gills. Some of the extracts were sensitive to proteinase K treatment, indicating antibacterial peptides and/or proteins. Lysozyme-like activity and toxic activity against Artemia salina nauplii was detected in fractions from the gills, mantle, muscle, and haemocytes. Results from this study indicate that M. modiolus is a promising source for identifying novel drug lead compounds. PMID:15050841
Haug, Tor; StensvÕg, Klara; Olsen M, žrjan M; Sandsdalen, Erling; Styrvold, Olaf B
Development and validation of an ultra high performance liquid chromatography tandem mass spectrometry method for simultaneous determination of sulfonamides, quinolones and benzimidazoles in bovine milk.
A simple, sensitive and reliable analytical method was developed for the simultaneous determination of 38 veterinary drugs (18 sulfonamides, 11 quinolones and 9 benzimidazoles) and 8 metabolites of benzimidazoles in bovine milk by ultra high performance liquid chromatography-positive electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Samples were extracted with acidified acetonitrile, cleaned up with Oasis(«) MCX cartridges, and analyzed by LC-MS/MS on an Acquity UPLC(«) BEH C18 column with gradient elution. The method allows such multi-analyte measurements within a 13min runtime while the specificity is ensured through the MRM acquisition mode. The method was validated according to the European Commission Decision 2002/657/EC determining specificity, decision limit (CC?), detection capability (CC?), recovery, precision, linearity and stability. For compounds which have MRLs in bovine milk, the CC? values fall into a range from 11 to 115?g/kg, and the CC? values fall within a range of 12-125?g/kg. For compounds which have not MRLs in bovine milk, the CC? values fall into a range from 0.01 to 0.08?g/kg, and the CC? values fall within a range of 0.02-0.11?g/kg. The mean recoveries of the 46 analytes were between 87 and 119%. The calculated RSD values of repeatability and within-laboratory reproducibility experiments were below 11% and 15% for the 46 compounds, respectively. The method was demonstrated to be suitable for the simultaneous determination of sulfonamides, quinolones and benzimidazoles in bovine milk. PMID:24887592
Hou, Xiao-Lin; Chen, Guo; Zhu, Li; Yang, Ting; Zhao, Jian; Wang, Lei; Wu, Yin-Liang
Antibacterial activity of amphiphilic tobramycin.
Amphiphilic aminoglycoside antimicrobials are an emerging class of new antibacterial agents with novel modes of action. Previous studies have shown that amphiphilic neomycin-B and kanamycin-A analogs restore potent antibacterial activity against Gram-positive neomycin-B- and kanamycin-A-resistant organisms. In this paper, we investigated the antibacterial properties of a series of amphiphilic tobramycin analogs. We prepared tobramycin-lipid conjugates, as well as tobramycin-peptide triazole conjugates, and studied their antibacterial activities against a panel of Gram-positive and Gram-negative bacterial strains, including isolates obtained from Canadian hospitals. Our results demonstrate that the antibacterial activity of amphiphilic tobramycin is greatly affected by the length and nature of the hydrophobic lipid tail, whereas the nature of the polycationic headgroup or the number of cationic charges appear to be less important. Replacement of the hydrophobic tail by a fluorinated lipid confers good activity against two Pseudomonas strains and reduces hemolytic activity. However, susceptibility studies in the presence of bovine serum albumin indicate that all amphiphilic tobramycin analogs are strongly protein-bound, leading to a typical four- to eight-fold increase in MIC. PMID:22781280
Dhondikubeer, Ramesh; Bera, Smritilekha; Zhanel, George G; Schweizer, Frank
Substituted Hydroxyapatites with Antibacterial Properties
Reconstructive surgery is presently struggling with the problem of infections located within implantation biomaterials. Of course, the best antibacterial protection is antibiotic therapy. However, oral antibiotic therapy is sometimes ineffective, while administering an antibiotic at the location of infection is often associated with an unfavourable ratio of dosage efficiency and toxic effect. Thus, the present study aims to find a new factor which may improve antibacterial activity while also presenting low toxicity to the human cells. Such factors are usually implemented along with the implant itself and may be an integral part of it. Many recent studies have focused on inorganic factors, such as metal nanoparticles, salts, and metal oxides. The advantages of inorganic factors include the ease with which they can be combined with ceramic and polymeric biomaterials. The following review focuses on hydroxyapatites substituted with ions with antibacterial properties. It considers materials that have already been applied in regenerative medicine (e.g., hydroxyapatites with silver ions) and those that are only at the preliminary stage of research and which could potentially be used in implantology or dentistry. We present methods for the synthesis of modified apatites and the antibacterial mechanisms of various ions as well as their antibacterial efficiency. PMID:24949423
Kolmas, Joanna; Groszyk, Ewa; Kwiatkowska-R¾?ycka, Dagmara
Cancer chemotherapy was introduced at the same time as antibacterial chemotherapy but has not been nearly such a success.\\u000a However, there is a growing optimism in oncology today due to the introduction of several more or less target-specific drugs\\u000a as complements to the conventional cytotoxic drugs introduced half a century ago. The success in the treatment of chronic\\u000a myelogenous leukemia
Curt Peterson
Molecular mechanisms of quinolone, macrolide, and tetracycline resistance among Campylobacter isolates from initial stages of broiler production.
The aim of this study was to investigate the resistance mechanisms of quinolones, macrolides and tetracycline in campylobacter isolates from grandparent and parent broiler breeders in Spain. Twenty-six isolates were investigated for quinolone resistance, three isolates for macrolide resistance and 39 for tetracycline resistance. All of the quinolone-resistant isolates possessed the mutation Thr86Ile in the quinolone resistance-determining region of gyrA and one isolate possessed the mutation Pro104Ser. Only one Campylobacter coli population (defined by restriction fragment length polymorphism-polymerase chain reaction of flaA and pulsed field gel electrophoresis) was resistant to erythromycin, and the mutation A2075G (23S rDNA) was responsible for macrolide resistance. The tetO gene was found in all of the tetracycline-resistant isolates. Twenty-two out of the 39 isolates investigated by Southern blot possessed chromosomic location of tetO and 17 were located on plasmids. Most of the plasmids with tetO were of around 60 kb and conjugation was demonstrated in a selection of them. In conclusion, we showed that Thr86Ile is highly prevalent in quinolone-resistant isolates as well as mutation A2075G in macrolide-resistant isolates of poultry origin. More variability was found for tetO. The possibility of horizontal transmission of tetO among campylobacter isolates is also an issue of concern in public health. PMID:24689432
Pķrez-Boto, D; Herrera-Le¾n, S; GarcĒa-Pe±a, F J; Abad-Moreno, J C; Echeita, M A
Antibacterial Biomimetic Hybrid Films.
In this work, we present a novel method to prepare a hybrid coating based on dextran grafted to a substrate and embedded with silver nanoparticles (Ag NPs). First, the Ag NPs are synthesized in situ in the presence of oxidized dextran in solution. Second, the oxidized dextran is exposed to an amine functionalized surface resulting in the simultaneous grafting of dextran and the trapping of Ag NPs within the layer. The NP loading is controlled by the concentration of silver nitrate, which is 2 mM (DEX-Ag2) and 5 mM (DEX-Ag5). The dried film thickness increases with silver nitrate concentration from 2 nm for dextran to 7 nm and 12 nm for DEX-Ag2 and DEX-Ag5, respectively. The grafted dextran film displays features with a diameter and height of ~ 50 nm and 2 nm, respectively. For the DEX-Ag2 and DEX-Ag5, the dextran features as well as individual Ag NPs (~ 5 nm) and aggregates of Ag NPs are observed. Larger and more irregular aggregates are observed for DEX-Ag5. Overall, the Ag NPs are embedded in the dextran film as suggested by AFM and UVO studies. In terms of its antimicrobial activity, DEX-Ag2 resists bacterial adhesion to a greater extent than DEX-Ag5, which in turn is better than dextran and silicon. Because these antibacterial hybrid coatings can be grafted to a variety of surfaces, many biomedical applications can be envisioned, ranging from coating implants to catheters. PMID:23807896
Ferrer, M Carme Coll; Hickok, Noreen J; Eckmann, David M; Composto, Russell J
Antibacterial Biomimetic Hybrid Films
In this work, we present a novel method to prepare a hybrid coating based on dextran grafted to a substrate and embedded with silver nanoparticles (Ag NPs). First, the Ag NPs are synthesized in situ in the presence of oxidized dextran in solution. Second, the oxidized dextran is exposed to an amine functionalized surface resulting in the simultaneous grafting of dextran and the trapping of Ag NPs within the layer. The NP loading is controlled by the concentration of silver nitrate, which is 2 mM (DEX-Ag2) and 5 mM (DEX-Ag5). The dried film thickness increases with silver nitrate concentration from 2 nm for dextran to 7 nm and 12 nm for DEX-Ag2 and DEX-Ag5, respectively. The grafted dextran film displays features with a diameter and height of ~ 50 nm and 2 nm, respectively. For the DEX-Ag2 and DEX-Ag5, the dextran features as well as individual Ag NPs (~ 5 nm) and aggregates of Ag NPs are observed. Larger and more irregular aggregates are observed for DEX-Ag5. Overall, the Ag NPs are embedded in the dextran film as suggested by AFM and UVO studies. In terms of its antimicrobial activity, DEX-Ag2 resists bacterial adhesion to a greater extent than DEX-Ag5, which in turn is better than dextran and silicon. Because these antibacterial hybrid coatings can be grafted to a variety of surfaces, many biomedical applications can be envisioned, ranging from coating implants to catheters. PMID:23807896
Ferrer, M. Carme Coll; Hickok, Noreen J.; Eckmann, David M.; Composto, Russell J.
Antimycobacterial and Antibacterial Activity of Allium sativum Bulbs
Tuberculosis is one of the major public health problems faced globally. Resistance of Mycobacterium tuberculosis to antitubercular agents has called for an urgent need to investigate newer drugs to combat tuberculosis. Garlic (Allium sativum) is an edible plant which has generated a lot of curiosity throughout human history as a medicinal plant. Garlic contains sulfur compounds like allicin, ajoene, allylmethyltrisulfide, diallyltrisulfide, diallyldisulphide and others which exhibit various biological properties like antimicrobial, anticancer, antioxidant, immunomodulatory, antiinflammatory, hypoglycemic, and cardiovascular effects. According to various traditional systems of medicine, garlic is one of the established remedies for tuberculosis. The objective of the current study was to investigate in vitro antimycobacterial activity as well as anti-bacterial activity of various extracts rich in specific phytoconstituents from garlic. Preparation of garlic extracts was done based on the chemistry of the constituents and their stability. The estimation of in vitro antimycobacterial activity of different garlic extracts was done using Resazurin microtire plate assay technique whereas activity of garlic oil was evaluated by colony count method. The antibacterial activity of extracts and oil was estimated by zone of inhibition method. Extracts of garlic rich in allicin and ajoene showed appreciable antimycobacterial activity as compared to standard drugs. Garlic oil demonstrated significant antibacterial activity, particularly against methicillin-resistant Staphylococcus aureus. PMID:25035540
Viswanathan, V.; Phadatare, A. G.; Mukne, Alka
Activity of Gemifloxacin against Quinolone-Resistant Streptococcus pneumoniae Strains In Vitro and in a Mouse Pneumonia Model
Gemifloxacin is a novel fluoronaphthyridone quinolone with enhanced in vitro activity against Streptococcus pneumoniae. We investigated the activities of gemifloxacin and trovafloxacin, their abilities to select for resistance in vitro and in vivo, and their efficacies in a mouse model of acute pneumonia. Immunocompetent Swiss mice were infected with 105 CFU of a virulent, encapsulated S. pneumoniae strain, P-4241, or its isogenic parC, gyrA, parC gyrA, and efflux mutant derivatives (serotype 3); and leukopenic mice were infected with 107 CFU of two poorly virulent clinical strains (serotype 11A) carrying either a parE mutation or a parC, gyrA, and parE triple mutation. The drugs were administered six times every 12 h, starting at either 3 or 18 h postinfection. In vitro, gemifloxacin was the most potent agent against strains with and without acquired resistance to fluoroquinolones. While control mice died within 6 days, gemifloxacin at doses of 25 and 50 mg/kg of body weight was highly effective (survival rates, 90 to 100%) against the wild-type strain and against mutants harboring a single mutation, corresponding to area under the time-versus-serum concentration curve at 24 h (AUC24)/MIC ratios of 56.5 to 113, and provided a 40% survival rate against a mutant with a double mutation (parC and gyrA). A total AUC24/MIC ratio of 28.5 was associated with poor efficacy and the emergence of resistant mutants. Trovafloxacin was as effective as gemifloxacin against mutants with single mutations but did not provide any protection against the mutant with double mutations, despite treatment with a high dose of 200 mg/kg. Gemifloxacin preferentially selected for parC mutants both in vitro and in vivo. PMID:15728901
Azoulay-Dupuis, E.; Bķdos, J. P.; Mohler, J.; Moine, P.; Cherbuliez, C.; Peytavin, G.; Fantin, B.; K÷hler, T.
In vitro and in vivo antibacterial activities of DC-159a, a new fluoroquinolone.
DC-159a is a new 8-methoxy fluoroquinolone that possesses a broad spectrum of antibacterial activity, with extended activity against gram-positive pathogens, especially streptococci and staphylococci from patients with community-acquired infections. DC-159a showed activity against Streptococcus spp. (MIC(90), 0.12 microg/ml) and inhibited the growth of 90% of levofloxacin-intermediate and -resistant strains at 1 microg/ml. The MIC 90s of DC-159a against Staphylococcus spp. were 0.5 microg/ml or less. Against quinolone- and methicillin-resistant Staphylococcus aureus strains, however, the MIC 90 of DC-159a was 8 microg/ml. DC-159a was the most active against Enterococcus spp. (MIC 90, 4 to 8 microg/ml) and was more active than the marketed fluoroquinolones, such as levofloxacin, ciprofloxacin, and moxifloxacin. The MIC 90s of DC-159a against Haemophilus influenzae, Moraxella catarrhalis, and Klebsiella pneumoniae were 0.015, 0.06, and 0.25 microg/ml, respectively. The activity of DC-159a against Mycoplasma pneumoniae was eightfold more potent than that of levofloxacin. The MICs of DC-159a against Chlamydophila pneumoniae were comparable to those of moxifloxacin, and DC-159a was more potent than levofloxacin. The MIC 90s of DC-159a against Peptostreptococcus spp., Clostridium difficile, and Bacteroides fragilis were 0.5, 4, and 2 microg/ml, respectively; and among the quinolones tested it showed the highest level of activity against anaerobic organisms. DC-159a demonstrated rapid bactericidal activity against quinolone-resistant Streptococcus pneumoniae strains both in vitro and in vivo. In vitro, DC-159a showed faster killing than moxifloxacin and garenoxacin. The bactericidal activity of DC-159a in a murine muscle infection model was revealed to be superior to that of moxifloxacin. These activities carried over to the in vivo efficacy in the murine pneumonia model, in which treatment with DC-159a led to bactericidal activity superior to those of the other agents tested. PMID:17938194
Hoshino, Kazuki; Inoue, Kazue; Murakami, Yoichi; Kurosaka, Yuichi; Namba, Kenji; Kashimoto, Yoshinori; Uoyama, Saori; Okumura, Ryo; Higuchi, Saito; Otani, Tsuyoshi
Improved bactericidal activity of Q-35 against quinolone-resistant staphylococci.
The bactericidal effects of Q-35, sparfloxacin, tosufloxacin, and ofloxacin on 18 strains of methicillin-resistant Staphylococcus aureus (MRSA) and 3 strains of Staphylococcus epidermidis were studied by a viable-count method. Staphylococci as used in this study were clearly divided into two groups with respect to their susceptibilities to sparfloxacin. MICs of Q-35 and tosufloxacin were 0.05 to 0.78 microgram/ml for sparfloxacin-susceptible strains (MICs, 0.05 to 0.2 microgram/ml) and 1.56 to 12.5 micrograms/ml for sparfloxacin-resistant strains (6.25 to 25 micrograms/ml). All the sparfloxacin-resistant strains of MRSA tested contained the gyrA mutation at codon 84. Time-kill studies showed that Q-35 decreased the viable counts from approximately 10(7) CFU/ml to 10(3) to 10(5) CFU/ml within 3 h at concentrations greater than the MICs against both sparfloxacin-susceptible and -resistant strains. In contrast, sparfloxacin, tosufloxacin, and ofloxacin produced bacteriostatic effects at 3 h after exposure against sparfloxacin-resistant strains at concentrations which were greater than the respective MICs, whereas these quinolones were bactericidal against sparfloxacin-susceptible strains. The rapid bactericidal activities of Q-35 against sparfloxacin-resistant MRSA were reduced when the methoxy group of Q-35 at the 8 position was substituted with fluorine or hydrogen. Thus, our data suggest that the introduction of a methoxy group into the 8 position of quinolones contributes to the bactericidal activities of fluoroquinolones against quinolone-resistant staphylococci. PMID:7492097
Ito, T; Matsumoto, M; Nishino, T
Improved bactericidal activity of Q-35 against quinolone-resistant staphylococci.
The bactericidal effects of Q-35, sparfloxacin, tosufloxacin, and ofloxacin on 18 strains of methicillin-resistant Staphylococcus aureus (MRSA) and 3 strains of Staphylococcus epidermidis were studied by a viable-count method. Staphylococci as used in this study were clearly divided into two groups with respect to their susceptibilities to sparfloxacin. MICs of Q-35 and tosufloxacin were 0.05 to 0.78 microgram/ml for sparfloxacin-susceptible strains (MICs, 0.05 to 0.2 microgram/ml) and 1.56 to 12.5 micrograms/ml for sparfloxacin-resistant strains (6.25 to 25 micrograms/ml). All the sparfloxacin-resistant strains of MRSA tested contained the gyrA mutation at codon 84. Time-kill studies showed that Q-35 decreased the viable counts from approximately 10(7) CFU/ml to 10(3) to 10(5) CFU/ml within 3 h at concentrations greater than the MICs against both sparfloxacin-susceptible and -resistant strains. In contrast, sparfloxacin, tosufloxacin, and ofloxacin produced bacteriostatic effects at 3 h after exposure against sparfloxacin-resistant strains at concentrations which were greater than the respective MICs, whereas these quinolones were bactericidal against sparfloxacin-susceptible strains. The rapid bactericidal activities of Q-35 against sparfloxacin-resistant MRSA were reduced when the methoxy group of Q-35 at the 8 position was substituted with fluorine or hydrogen. Thus, our data suggest that the introduction of a methoxy group into the 8 position of quinolones contributes to the bactericidal activities of fluoroquinolones against quinolone-resistant staphylococci. PMID:7492097
Ito, T; Matsumoto, M; Nishino, T
Crude ethanolic extracts of fruits, leaves, stems and roots of Citrulus colocynthis Schrad were examined for their antibacterial potentialities against Gram positive and Gram negative bacilli. Ethanolic extracts of fruits, leaves, stems and roots were found to be active against Gram positive bacilli, viz., Bacilus pumilus and Staphylococcus aureus, while fruit and root extracts in double strength gave positive results
Antibacterial peptides isolated from insects
Insects are amazingly resistant to bacterial infections. To combat pathogens, insects rely on cellular and humoral mechanisms, innate immunity being dominant in the latter category. Upon detection of bacteria, a complex genetic cascade is activated, which ultimately results in the synthesis of a battery of antibacterial peptides and their release into the haemolymph. The peptides are usually basic in character
Quinolone-benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer disease.
Design, synthesis and evaluation of new acetylcholinesterase inhibitors by combining quinolinecarboxamide to a benzylpiperidine moiety are described. Then, a series of hybrids have been developed by introducing radical scavengers. Molecular modeling was performed and structure activity relationships are discussed. Among the series, most potent compounds show effective AchE inhibitions, high selectivities over butyrylcholinesterase and high radical scavenging activities. On the basis of this work, the ability of quinolone derivatives to serve in the design of N-benzylpiperidine linked multipotent molecules for the treatment of Alzheimer Disease has been established. PMID:24657052
Pudlo, Marc; Luzet, Vincent; Isma'li, Lhassane; Tomassoli, Isabelle; Iutzeler, Anne; Refouvelet, Bernard
Effects of cyclic lipodepsipeptide structural modulation on stability, antibacterial activity and human cell toxicity
Bacterial infections are becoming increasingly difficult to treat due to the development and spread of antibiotic resistance. Therefore, identifying novel antibacterial targets and new antibacterial agents capable of treating infections from drug-resistant bacteria is of vital importance. Structurally simple, yet potent fusaricidin or LI-F class of natural products represents a particularly attractive source of candidates for the development of new antibacterial agents. We have synthesized eighteen fusaricidin/LI-F analogs and investigated the effect of their structure modification on conformation, serum stability, antibacterial activity and human cell toxicity. Our findings show that substitution of an ester bond in depsipeptides with an amide bond may afford equally potent analogs with improved stability and greatly decreased cytotoxicity. Lower overall hydrophobicity/amphiphilicity of amide analogs in comparison to their parent depsipeptides, as indicated by the HPLC retention times, may explain dissociation of antibacterial activity and human cell cytotoxicity. These results indicate that amide analogs may have significant advantages over fusaricidin/LI-F natural products and their depsipeptide analogs as lead structures for the development of new antibacterial agents. PMID:22392790
Bionda, Nina; Stawikowski, Maciej; Stawikowska, Roma; Cudic, Marķ; L¾pez-Vallejo, Fabian; Treitl, Daniela; Medina-Franco, Josķ
Shikimic acid, a base compound for the formulation of swine/avian flu drug: statistical optimization, fed-batch and scale up studies along with its application as an antibacterial agent.
The sudden outbreak of swine flu has increased the global demand of shikimic acid which is an industrially interesting compound, as it is used as a key starting material for the synthesis of a neuraminidase inhibitor Tamiflu(«), for the treatment of antiviral infections such as swine flu. Statistical optimization and evaluation of medium components for the production of shikimic acid by Citrobacter freundii is addressed in the present investigation. Plackett-Burman design was applied for the screening of the most significant variables affecting shikimic acid production, where glucose, asparagine, KH2PO4, CaCO3 and agitation rate were the most significant factors. Response surface methodology was also employed to study the interaction among the most significant variables through which shikimic acid production increased to 12.76 g/L. Further, fed-batch studies resulted in the production of 22.32 g/L of shikimic acid. The scalability of the process was also confirmed by running 14 L bioreactor (7.5 L production medium) where 20.12 g/L of shikimic acid was produced. In addition the antibacterial activity of the shikimic acid produced was analysed against four Gram positive and four Gram negative bacteria and it was found to have a greater inhibition effect against the Gram negative bacteria. PMID:25563634
Tripathi, P; Rawat, G; Yadav, S; Saxena, R K
Interaction of vanadium (IV) solvates (L) with second-generation fluoroquinolone antibacterial drug ciprofloxacin: spectroscopic, structure, thermal analyses, kinetics and biological evaluation (L=An, DMF, Py and Et3N).
The preparation and characterization of the new solid complexes [VO(CIP)2L]SO4?nH2O, where L=aniline (An), dimethylformamide (DMF), pyridine (Py) and triethylamine (Et3N) in the reaction of ciprofloxacin (CIP) with VO(SO4)2Ę2H2O in ethanol. The isolated complexes have been characterized with their melting points, elemental analysis, IR spectroscopy, magnetic properties, conductance measurements, UV-Vis. and (1)H NMR spectroscopic methods and thermal analyses. The results supported the formation of the complexes and indicated that ciprofloxacin reacts as a bidentate ligand bound to the vanadium ion through the pyridone oxygen and one carboxylato oxygen. The activation energies, E(*); entropies, ?S(*); enthalpies, ?H(*); Gibbs free energies, ?G(*), of the thermal decomposition reactions have been derived from thermo gravimetric (TGA) and differential thermo gravimetric (DTG) curves, using Coats-Redfern and Horowitz-Metzeger methods. The lowest energy model structure of each complex has been proposed by using the density functional theory (DFT) at the B3LYP/CEP-31G level of theory. The ligand and their metal complexes were also evaluated for their antibacterial activity against several bacterial species, such as Bacillus Subtilis (B. Subtilis), Staphylococcus aureus (S. aureus), Nesseria Gonorrhoeae (N. Gonorrhoeae), Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli). PMID:24762540
Zordok, Wael A
Interaction of vanadium (IV) solvates (L) with second-generation fluoroquinolone antibacterial drug ciprofloxacin: Spectroscopic, structure, thermal analyses, kinetics and biological evaluation (L = An, DMF, Py and Et3N)
NASA Astrophysics Data System (ADS)
The preparation and characterization of the new solid complexes [VO(CIP)2L]SO4?nH2O, where L = aniline (An), dimethylformamide (DMF), pyridine (Py) and triethylamine (Et3N) in the reaction of ciprofloxacin (CIP) with VO(SO4)2Ę2H2O in ethanol. The isolated complexes have been characterized with their melting points, elemental analysis, IR spectroscopy, magnetic properties, conductance measurements, UV-Vis. and 1H NMR spectroscopic methods and thermal analyses. The results supported the formation of the complexes and indicated that ciprofloxacin reacts as a bidentate ligand bound to the vanadium ion through the pyridone oxygen and one carboxylato oxygen. The activation energies, E*; entropies, ?S*; enthalpies, ?H*; Gibbs free energies, ?G*, of the thermal decomposition reactions have been derived from thermo gravimetric (TGA) and differential thermo gravimetric (DTG) curves, using Coats-Redfern and Horowitz-Metzeger methods. The lowest energy model structure of each complex has been proposed by using the density functional theory (DFT) at the B3LYP/CEP-31G level of theory. The ligand and their metal complexes were also evaluated for their antibacterial activity against several bacterial species, such as Bacillus Subtilis (B. Subtilis), Staphylococcus aureus (S. aureus), Nesseria Gonorrhoeae (N. Gonorrhoeae), Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli).
Zordok, Wael A.
Recent Advances in Drugs and Prodrugs Design of Chitosan
The aim of this review is to outline the recent advances in chitosan molecular modeling, especially its usage as a prodrug or drug in a field of antibacterial, anticarcinogenic and antioxidant activity. Polymeric materials like peptides, polysaccharides and other natural products have recently attracted attention as biodegradabile drug car- riers. They can optimize clinical drug application, minimize the undesirable drug
J. Vinsova; E. Vavrikova
Antibacterial activity of traditional medicinal plants used by Haudenosaunee peoples of New York State
BACKGROUND: The evolution and spread of antibiotic resistance, as well as the evolution of new strains of disease causing agents, is of great concern to the global health community. Our ability to effectively treat disease is dependent on the development of new pharmaceuticals, and one potential source of novel drugs is traditional medicine. This study explores the antibacterial properties of
Frank M Frey; Ryan Meyers
Antibacterial resistant bacteria in surficial sediments near salmon net-cage farms in Puget Sound, Washington
Antibacterials are used in medicated fish feed at fish farms located in Puget Sound, Washington. These compounds include oxytetracycline (OTC), amoxycillin, and Romet« 30 (a drug composed of sulfadimethioxine and ormetoprim). In this study we collected surficial sediment samples at three different commercial salmon net-cage farms during the summer and early fall of 1992. The three different farms varied in
Russell P Herwig; James P Gray; Donald P Weston
Comparing anti-HIV, antibacterial, antifungal, micellar, and cytotoxic properties of tricarboxylato dendritic amphiphiles
Comparing anti-HIV, antibacterial, antifungal, micellar, and cytotoxic properties of tricarboxylato homologous series had modest anti-HIV activity (EC50 = 110Ł130 lM). Amphiphile 2(18) had the best anti, United States b Department of Physical Chemistry of Drugs, Faculty of Pharmacy, Comenius University
Falkinham, Joseph
Antibiotics threaten wildlife: circulating quinolone residues and disease in Avian scavengers.
Antibiotic residues that may be present in carcasses of medicated livestock could pass to and greatly reduce scavenger wildlife populations. We surveyed residues of the quinolones enrofloxacin and its metabolite ciprofloxacin and other antibiotics (amoxicillin and oxytetracycline) in nestling griffon Gyps fulvus, cinereous Aegypius monachus and Egyptian Neophron percnopterus vultures in central Spain. We found high concentrations of antibiotics in the plasma of many nestling cinereous (57%) and Egyptian (40%) vultures. Enrofloxacin and ciprofloxacin were also found in liver samples of all dead cinereous vultures. This is the first report of antibiotic residues in wildlife. We also provide evidence of a direct association between antibiotic residues, primarily quinolones, and severe disease due to bacterial and fungal pathogens. Our results indicate that, by damaging the liver and kidney and through the acquisition and proliferation of pathogens associated with the depletion of lymphoid organs, continuous exposure to antibiotics could increase mortality rates, at least in cinereous vultures. If antibiotics ingested with livestock carrion are clearly implicated in the decline of the vultures in central Spain then it should be considered a primary concern for conservation of their populations. PMID:18197254
Lemus, Jes·s A; Blanco, Guillermo; Grande, Javier; Arroyo, Bernardo; GarcĒa-Montijano, Marino; MartĒnez, FelĒx
Antibiotics Threaten Wildlife: Circulating Quinolone Residues and Disease in Avian Scavengers
Antibiotic residues that may be present in carcasses of medicated livestock could pass to and greatly reduce scavenger wildlife populations. We surveyed residues of the quinolones enrofloxacin and its metabolite ciprofloxacin and other antibiotics (amoxicillin and oxytetracycline) in nestling griffon Gyps fulvus, cinereous Aegypius monachus and Egyptian Neophron percnopterus vultures in central Spain. We found high concentrations of antibiotics in the plasma of many nestling cinereous (57%) and Egyptian (40%) vultures. Enrofloxacin and ciprofloxacin were also found in liver samples of all dead cinereous vultures. This is the first report of antibiotic residues in wildlife. We also provide evidence of a direct association between antibiotic residues, primarily quinolones, and severe disease due to bacterial and fungal pathogens. Our results indicate that, by damaging the liver and kidney and through the acquisition and proliferation of pathogens associated with the depletion of lymphoid organs, continuous exposure to antibiotics could increase mortality rates, at least in cinereous vultures. If antibiotics ingested with livestock carrion are clearly implicated in the decline of the vultures in central Spain then it should be considered a primary concern for conservation of their populations. PMID:18197254
Lemus, Jes·s ┴.; Blanco, Guillermo; Grande, Javier; Arroyo, Bernardo; GarcĒa-Montijano, Marino; MartĒnez, FelĒx
Lack of efflux mediated quinolone resistance in Salmonella enterica serovars Typhi and Paratyphi A.
Salmonella enterica serovars Typhi and Paratyphi A isolates from human patients in France displaying different levels of resistance to quinolones or fluoroquinolones were studied for resistance mechanisms to these antimicrobial agents. All resistant isolates carried either single or multiple target gene mutations (i.e., in gyrA, gyrB, or parC) correlating with the resistance levels observed. Active efflux, through upregulation of multipartite efflux systems, has also been previously reported as contributing mechanism for other serovars. Therefore, we investigated also the occurrence of non-target gene mutations in regulatory regions affecting efflux pump expression. However, no mutation was detected in these regions in both Typhi and Paratyphi isolates of this study. Besides, no overexpression of the major efflux systems was observed for these isolates. Nevertheless, a large deletion of 2334 bp was identified in the acrS-acrE region of all S. Typhi strains but which did not affect the resistance phenotype. As being specific to S. Typhi, this deletion could be used for specific molecular detection purposes. In conclusion, the different levels of quinolone or FQ resistance in both S. Typhi and S. Paratyphi A seem to rely only on target modifications. PMID:24478769
Baucheron, Sylvie; Monchaux, Isabelle; Le Hello, Simon; Weill, Franńois-Xavier; Cloeckaert, Axel
Role of the Pseudomonas quinolone signal (PQS) in sensitising Pseudomonas aeruginosa to UVA radiation.
One of the main stress factors that bacteria face in the environment is solar ultraviolet-A (UVA) radiation, which leads to lethal effects through oxidative damage. The aim of this work was to investigate the role of 2-heptyl-3-hydroxi-4-quinolone (the Pseudomonas quinolone signal or PQS) in the response of Pseudomonas aeruginosa to UVA radiation. PQS is an intercellular quorum sensing signal associated to membrane vesicles which, among other functions, regulates genes related to iron acquisition, forms stable complexes with iron and participates in oxidative phenomena. UVA exposure of the wild-type PAO1 strain and a pqsA mutant unable to produce PQS revealed a sensitising role for this signal. Research into the mechanism involved in this phenomenon revealed that catalase, an essential factor in the UVA defence, is not related to PQS-mediated UVA sensitivity. Absorption of UVA by PQS produced its own photo-degradation, oxidation of the probe 2',7'- dichlorodihydrofluorescein and generation of singlet oxygen and superoxide anion, suggesting that this signal could be acting as an endogenous photosensitiser. The results presented in this study could explain the high sensitivity to UVA of P. aeruginosa when compared to enteric bacteria. PMID:25535873
Pezzoni, Magdalena; Meichtry, MartĒn; Pizarro, Ram¾n A; Costa, Cristina S
Exploring MIA-QSARs' for Antimalarial Quinolon-4(1H)-Imines.
A series of quinolon-4(1H)-imines have been recently discovered as antimalarials, targeting both the exoerythrocytic and erythrocytic stages of the parasite's development stages, which correspond to the phase of clinical symptoms. Endowed with chemical and metabolic stability, the quinolon-4(1H)- imines are thus presented as promissory dual-stage antimalarials. Three versions of multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR) methods, namely traditional MIA-QSAR, augmented MIA-QSAR (aug-MIA-QSAR) and color-encoded aug-MIA-QSAR (aug- MIA-QSARcolor), were applied to model the antimalarial activities in this series of compounds. The multiple linear regression models indicated that the aug-MIA-QSAR method is more predictive and reliable than the others (R(2) = 0.8079, R(2)cv = 0.6647 and R(2)pred = 0.9691) for this series of compounds. The selected aug- MIA-QSAR descriptors were used for pattern recognition using discriminant analysis by partial least squares (PLS-DA), in order to separate compounds with low, moderate and high bioactivities. PMID:25543687
Duarte, Mariene H; Barigye, Stephen J; Freitas, Matheus P
Quinolone and indole alkaloids from the fruits of Euodia rutaecarpa and their cytotoxicity against two human cancer cell lines.
Four quinolone alkaloids (1-4) and three indole alkaloids (20-22), together with 30 known alkaloids (5-19, 23-37), were isolated from the fruits of Euodia rutaecarpa. Their structures were established by spectroscopic analyses. The in vitro cytotoxic activities of these alkaloids against leukaemia HL-60 and prostate cancer PC-3 cell lines were evaluated. PMID:25457491
Zhao, Nan; Li, Zhan-Lin; Li, Da-Hong; Sun, Ya-Ting; Shan, Dong-Ting; Bai, Jiao; Pei, Yue-Hu; Jing, Yong-Kui; Hua, Hui-Ming
Emerging Plasmid-Mediated Quinolone Resistance Associated with the qnr Gene in Klebsiella pneumoniae Clinical Isolates in the United States
Although quinolone resistance commonly results from chromosomal mutation, recent studies indicate that such resistance can also be transferred on plasmids carrying the gene responsible, qnr. One hundred ten ciprofloxacin-resistant clinical isolates of Klebsiella pneumoniae and Escherichia coli from the United States were screened for the qnr gene by PCR and Southern hybridization of plasmid DNA. Conjugation experiments were done with
Minggui Wang; Daniel F. Sahm; George A. Jacoby; David C. Hooper
Technology Transfer Automated Retrieval System (TEKTRAN)
Background: Commensal bacteria may serve as reservoirs of antibiotic resistance genes. The possibility that these may be transferred to zoonotic pathogens is under study. Resistance to Quinolones is of particular interest because of their value in treating severe human infections. Methods: Plain M...
Anti-bacterial monoclonal antibodies: back to the future?
Today's medicine has to deal with the emergence of multi-drug resistant bacteria, and is beginning to be confronted with pan-resistant microbes. This worsening inadequacy of the antibiotics concept, which has ruled infectious medicine in the last six decades creates an increasing unmet medical need that can be addressed by passive immunization. While past experience from the pre-antibiotic era with serum therapy was in many cases encouraging, antibacterial monoclonal antibodies have so far suffered high attrition rates in the clinic, generally from lack of efficacy. Yet, we believe that recent developments in a number of areas such as infectious disease pathogenesis research, translational medicine, mAb engineering, mAb manufacturing and rapid bedside diagnostics are converging to make the medium-term future permissive for antibacterial mAb development. Here, we review antibacterial mAb-based approaches that are or were in clinical development, and may potentially act as paradigms with regards to molecular targets, antibody formats and mode-of-action, pre-clinical validation and selection of most relevant patient populations, in order to increase the likelihood of successful product development in this field. PMID:22705202
Oleksiewicz, Martin B; Nagy, Gßbor; Nagy, Eszter
Recombinant bacteriophage lysins as antibacterials
With the increasing worldwide prevalence of antibiotic resistant bacteria, bacteriophage endolysins (lysins) represent a very promising novel alternative class of antibacterial in the fight against infectious disease. Lysins are phage-encoded peptidoglycan hydrolases which, when applied exogenously (as purified recombinant proteins) to Gram-positive bacteria, bring about rapid lysis and death of the bacterial cell. A number of studies have recently demonstrated the strong potential of these enzymes in human and veterinary medicine to control and treat pathogens on mucosal surfaces and in systemic infections. They also have potential in diagnostics and detection, bio-defence, elimination of food pathogens and control of phytopathogens. This review discusses the extensive research on recombinant bacteriophage lysins in the context of antibacterials, and looks forward to future development and potential. PMID:21327123
Fenton, Mark; Ross, Paul; McAuliffe, Olivia; O'Mahony, Jim
Cloning and Structure-Function Analyses of Quinolone- and Acridone-producing Novel Type III Polyketide Synthases from Citrus microcarpa*
Two novel type III polyketide synthases, quinolone synthase (QNS) and acridone synthase (ACS), were cloned from Citrus microcarpa (Rutaceae). The deduced amino acid sequence of C. microcarpa QNS is unique, and it shared only 56¢60% identities with C. microcarpa ACS, Medicago sativa chalcone synthase (CHS), and the previously reported Aegle marmelos QNS. In contrast to the quinolone- and acridone-producing A. marmelos QNS, C. microcarpa QNS produces 4-hydroxy-N-methylquinolone as the ōsingle productö by the one-step condensation of N-methylanthraniloyl-CoA and malonyl-CoA. However, C. microcarpa ACS shows broad substrate specificities and produces not only acridone and quinolone but also chalcone, benzophenone, and phloroglucinol from 4-coumaroyl-CoA, benzoyl-CoA, and hexanoyl-CoA, respectively. Furthermore, the x-ray crystal structures of C. microcarpa QNS and ACS, solved at 2.47- and 2.35-? resolutions, respectively, revealed wide active site entrances in both enzymes. The wide active site entrances thus provide sufficient space to facilitate the binding of the bulky N-methylanthraniloyl-CoA within the catalytic centers. However, the active site cavity volume of C. microcarpa ACS (760 ?3) is almost as large as that of M. sativa CHS (750 ?3), and ACS produces acridone by employing an active site cavity and catalytic machinery similar to those of CHS. In contrast, the cavity of C. microcarpa QNS (290 ?3) is significantly smaller, which makes this enzyme produce the diketide quinolone. These results as well as mutagenesis analyses provided the first structural bases for the anthranilate-derived production of the quinolone and acridone alkaloid by type III polyketide synthases. PMID:23963450
Mori, Takahiro; Shimokawa, Yoshihiko; Matsui, Takashi; Kinjo, Keishi; Kato, Ryohei; Noguchi, Hiroshi; Sugio, Shigetoshi; Morita, Hiroyuki; Abe, Ikuro
A Function of SmeDEF, the Major Quinolone Resistance Determinant of Stenotrophomonas maltophilia, Is the Colonization of Plant Roots
Quinolones are synthetic antibiotics, and the main cause of resistance to these antimicrobials is mutation of the genes encoding their targets. However, in contrast to the case for other organisms, such mutations have not been found in quinolone-resistant Stenotrophomonas maltophilia isolates, in which overproduction of the SmeDEF efflux pump is a major cause of quinolone resistance. SmeDEF is chromosomally encoded and highly conserved in all studied S. maltophilia strains; it is an ancient element that evolved over millions of years in this species. It thus seems unlikely that its main function would be resistance to quinolones, a family of synthetic antibiotics not present in natural environments until the last few decades. Expression of SmeDEF is tightly controlled by the transcriptional repressor SmeT. Our work shows that plant-produced flavonoids can bind to SmeT, releasing it from smeDEF and smeT operators. Antibiotics extruded by SmeDEF do not impede the binding of SmeT to DNA. The fact that plant-produced flavonoids specifically induce smeDEF expression indicates that they are bona fide effectors regulating expression of this resistance determinant. Expression of efflux pumps is usually downregulated unless their activity is needed. Since smeDEF expression is triggered by plant-produced flavonoids, we reasoned that this efflux pump may have a role in the colonization of plants by S. maltophilia. Our results showed that, indeed, deletion of smeE impairs S. maltophilia colonization of plant roots. Altogether, our results indicate that quinolone resistance is a recent function of SmeDEF and that colonization of plant roots is likely one original function of this efflux pump. PMID:24837376
GarcĒa-Le¾n, Guillermo; Hernßndez, Alvaro; Hernando-Amado, Sara; Alavi, Peyman; Berg, Gabriele
Thiourea derivatives incorporating a hippuric acid moiety: synthesis and evaluation of antibacterial and antifungal activities.
New series of thiourea derivatives incorporating a hippuric acid moiety have been synthesized through the reaction of 4-hippuric acid isothiocyanate with various nitrogen nucleophiles such as aliphatic amines, aromatic amines, sulfa drugs, aminopyrazoles, phenylhydrazine and hydrazides. The synthesized compounds were tested against bacterial and fungal strains. Most of compounds, such as 2-(4-(3-(3-bromophenyl)thioureido)benzamido)acetic acid and 2-(4-(3-(4-(N-pyrimidin-2-ylsulfamoyl)phenyl)thioureido)benzamido)acetic acid, showed significant antibacterial and antifungal activities. These compounds comprise a new class of promising broad-spectrum antibacterial and antifungal agents. PMID:23644194
Abbas, Samir Y; El-Sharief, Marwa A M Sh; Basyouni, Wahid M; Fakhr, Issa M I; El-Gammal, Eman W
Characterization of Ribosomal Binding and Antibacterial Activities Using Two Orthogonal High-Throughput Screens
We report here the affinity and antibacterial activity of a structurally similar class of neomycin dimers. The affinity of the dimer library for rRNA was established by using a screen that measures the displacement of fluorescein-neomycin (F-neo) probe from RNA. A rapid growth inhibition assay using a single drug concentration was used to examine the antibacterial activity. The structure-activity relationship data were then rapidly analyzed using a two-dimensional ribosomal binding-bacterial inhibition plot analysis. PMID:23856777
King, Ada; Watkins, Derrick; Kumar, Sunil; Ranjan, Nihar; Gong, Changjun; Whitlock, Jarred
[Resistance to antituberculous drugs].
Mycobacteria responsible for tuberculosis (M. tuberculosis, M. bovis, M. africanum) are susceptible to a very small number of antibiotics. As soon as these drugs were used in humans all gave rise to the selection of resistant mycobacteria. Study of the mechanisms of acquired resistance, with the help of the genetics of mycobacteria, led to a more accurate understanding of the mode of action of antituberculous drugs. The antibiotics isoniazid, pyrazinamide, ethionamide and ethambutol are mycobacteria-specific because they inhibit the synthesis of mycolic acids, which are specific constituants of the bacterial wall. Mutations responsible for resistance to these drugs affect genes coding for activator enzymes (katg for isoniazid, pncA for pyrazinamide) or genes coding for their target (inhA for isoniazid/ethionamide, embB for ethambutol). With rifamycins, aminosides and quinolones, mechanisms of action and resistance are the same for mycobacteria as for non-mycobacterial organisms. No plasmid or resistance transposon has been described in M. tuberculosis. Currently a test for the quick detection of resistance to rifampicin is widely available but in the future DNA chips may allow the simultaneous detection of multiple resistances. Monitoring of antituberculous drugs shows that in France the prevalence of multiresistance ( resistance to both isoniazid and rifampicin) is 0.5%, primary resistance (before treatment) is 9%, and secondary resistance (after treatment) is 16%. PMID:16129320
Veziris, N; Cambau, E; Sougakoff, W; Robert, J; Jarlier, V
A detailed study of antibacterial 3-acyltetramic acids and 3-acylpiperidine-2,4-diones.
Inspired by the core fragment of antibacterial natural products such as streptolydigin, 3-acyltetramic acids and 3-acylpiperidine-2,4-diones have been synthesised from the core heterocycle by direct acylation with the substituted carboxylic acids using a strategy which permits ready access to a structurally diverse compound library. The antibacterial activity of these systems has been established against a panel of Gram-positive and Gram-negative bacteria, with activity mostly against the former, which in some cases is very potent. Data consistent with modes of action against undecaprenylpyrophosphate synthase (UPPS) and/or RNA polymerase (RNAP) for a small subset of the library has been obtained. The most active compounds have been shown to exhibit binding at known binding sites of streptolydigin and myxopyronin at UPPS and RNAP. These systems offer potential for their antibacterial activity, and further demonstrate the use of natural products as biologically validated starting points for drug discovery. PMID:24838989
Jeong, Yong-Chul; Bikadi, Zsolt; Hazai, Eszter; Moloney, Mark G
SAR Studies for a New Class of Antibacterial NAD Biosynthesis Inhibitors
A new lead class of antibacterial drug-like NAD synthetase (NADs) inhibitors was previously identified from a virtual screening study. Here a solution-phase synthetic library of 76 compounds, analogs of the urea-sulfonamide 5838, was synthesized in parallel to explore SAR on the sulfonamide aryl group. All library members were tested for enzyme inhibition against NADs and nicotinic acid mononucleotide adenylyltransferase (NaMNAT), the last two enzymes in the biosynthesis of NAD, and for growth inhibition in a B. anthracis antibacterial assay. Most compounds that inhibited bacterial growth also showed inhibition against one of the enzymes tested. While only modest enhancements in the enzyme inhibition potency against NADs were observed, of significance was the observation that the antibacterial urea-sulfonamides more consistently inhibited NaMNAT. PMID:19408950
Moro, Whitney Beysselance; Yang, Zhengrong; Kane, Tasha A.; Zhou, Qingxian; Harville, Steve; Brouillette, Christie G.; Brouillette, Wayne J.
An antibacterial thiophene from Balsamorhiza sagittata.
Balsamorhiza sagittata, a species of ethnopharmacological interest in British Columbia, is reported to have antibacterial and antifungal properties. An antibacterial compound isolated from this species was identified as 7,10-epithio-7,9-tridecadiene-3,5,11-triyne-1,2-diol based on the HMQC and HMBC experiments. PMID:8720391
Matsuura, H; Saxena, G; Farmer, S W; Hancock, R E; Towers, G H
Antibacterial Household Products: Cause for Concern
The recent entry of products containing antibacterial agents into healthy households has escalated from a few dozen products in the mid-1990s to more than 700 today. Antibacterial products were developed and have been successfully used to prevent transmission of disease-causing microorganisms among patients, particularly in hospitals. They are now being added to products used in healthy households, even though an
Stuart B. Levy
Transformation of the Antibacterial Agent Sulfamethoxazole in
transformation during disinfection of such waters with free chlorine residuals. Introduction Sulfamethoxazole of antibacterial resistance has yet to be proven, singly and multiply antibacterial resistant bacteria have been water (8-11). The detection in aquatic environ- mental systems of resistant bacteria
Huang, Ching-Hua
The Relationship between Quinolone Exposures and Resistance Amplification Is Characterized by an Inverted U: a New Paradigm for Optimizing Pharmacodynamics To Counterselect Resistance
Received 17 March 2006\\/Returned for modification 9 August 2006\\/Accepted 31 October 2006 We determined the relationship between garenoxacin exposure and quinolone-resistant subpopulations for three bacterial isolates in an in vitro hollow-fiber infection model. An \\
Vincent H. Tam; Arnold Louie; Mark R. Deziel; Weiguo Liu; George L. Drusano
Non-heme dioxygenase catalyzes atypical oxidations of 6,7-bicyclic systems to form the 6,6-quinolone core of viridicatin-type fungal alkaloids.
The 6,6-quinolone scaffold of the viridicatin-type of fungal alkaloids are found in various quinolone alkaloids which often exhibit useful biological activities. Thus, it is of interest to identify viridicatin-forming enzymes and understand how such alkaloids are biosynthesized. Here an Aspergillal gene cluster responsible for the biosynthesis of 4'-methoxyviridicatin was identified. Detailed in?vitro studies led to the discovery of the dioxygenase AsqJ which performs two distinct oxidations: first desaturation to form a double bond and then monooxygenation of the double bond to install an epoxide. Interestingly, the epoxidation promotes non-enzymatic rearrangement of the 6,7-bicyclic core of 4'-methoxycyclopenin into the 6,6-quinolone viridicatin scaffold to yield 4'-methoxyviridicatin. The finding provides new insight into the biosynthesis of the viridicatin scaffold and suggests dioxygenase as a potential tool for 6,6-quinolone synthesis by epoxidation of benzodiazepinediones. PMID:25251934
Ishikawa, Noriyasu; Tanaka, Hidenori; Koyama, Fumi; Noguchi, Hiroshi; Wang, Clay C C; Hotta, Kinya; Watanabe, Kenji
Proteolytically activated anti-bacterial hydrogel microspheres
Hydrogels are finding increased clinical utility as advances continue to exploit their favorable material properties. Hydrogels can be adapted for many applications, including surface coatings and drug delivery. Anti-infectious surfaces and delivery systems that actively destroy invading organisms are alternative ways to exploit the favorable material properties offered by hydrogels. Sterilization techniques are commonly employed to ensure the materials are non-infectious upon placement, but sterilization is not absolute and infections are still expected. Natural, anti-bacterial proteins have been discovered which have the potential to act as anti-infectious agents; however, the proteins are toxic and need localized release to have therapeutic efficacy without toxicity. In these studies, we explore the use of the glutathione s-transferase (GST) to anchor the bactericidal peptide, melittin, to the surface of poly(ethylene glycol) diacrylate (PEGDA) hydrogel microspheres. We show that therapeutic levels of protein can be anchored to the surface of the microspheres using the GST anchor. We compared the therapeutic efficacy of recombinant melittin released from PEGDA microspheres to melittin. We found that, when released by an activating enzyme, thrombin, recombinant melittin efficiently inhibits growth of the pathogenic bacterium Streptococcus pyogenes as effectively as melittin created by solid phase peptide synthesis. We conclude that a GST protein anchor can be used to immobilize functional protein to PEGDA microspheres and the protein will remain immobilized under physiological conditions until the protein is enzymatically released. PMID:23816641
Buhrman, Jason S.; Cook, Laura C.; Rayahin, Jamie E.; Federle, Michael J.; Gemeinhart, Richard A.
A Conserved Suppressor Mutation in a Tryptophan Auxotroph Results in Dysregulation of Pseudomonas Quinolone Signal Synthesis
Pseudomonas aeruginosa is a common nosocomial pathogen that relies on three cell-to-cell signals to regulate multiple virulence factors. The Pseudomonas quinolone signal (PQS; 2-heptyl-3-hydroxy-4-quinolone) is one of these signals, and it is known to be important for P. aeruginosa pathogenesis. PQS is synthesized in a multistep reaction that condenses anthranilate and a fatty acid. In P. aeruginosa, anthranilate is produced via the kynurenine pathway and two separate anthranilate synthases, TrpEG and PhnAB, the latter of which is important for PQS synthesis. Others have previously shown that a P. aeruginosa tryptophan auxotroph could grow on tryptophan-depleted medium with a frequency of 10?5 to 10?6. These revertants produced more pyocyanin and had increased levels of phnA transcript. In this study, we constructed similar tryptophan auxotroph revertants and found that the reversion resulted from a synonymous G-to-A nucleotide mutation within pqsC. This change resulted in increased pyocyanin and decreased PQS, along with an increase in the level of the pqsD, pqsE, and phnAB transcripts. Reporter fusion and reverse transcriptase PCR studies indicated that a novel transcript containing pqsD, pqsE, and phnAB occurs in these revertants, and quantitative real-time PCR experiments suggested that the same transcript appears in the wild-type strain under nutrient-limiting conditions. These results imply that the PQS biosynthetic operon can produce an internal transcript that increases anthranilate production and greatly elevates the expression of the PQS signal response protein PqsE. This suggests a novel mechanism to ensure the production of both anthranilate and PQS-controlled virulence factors. PMID:24748618
Knoten, Claire A.; Wells, Greg; Coleman, James P.
Complete Proteome of a Quinolone-Resistant Salmonella Typhimurium Phage Type DT104B Clinical Strain
Salmonellosis is one of the most common and widely distributed foodborne diseases. The emergence of Salmonella strains that are resistant to a variety of antimicrobials is a serious global public health concern. Salmonella enterica serovar Typhimurium definitive phage type 104 (DT104) is one of these emerging epidemic multidrug resistant strains. Here we collate information from the diverse and comprehensive range of experiments on Salmonella proteomes that have been published. We then present a new study of the proteome of the quinolone-resistant Se20 strain (phage type DT104B), recovered after ciprofloxacin treatment and compared it to the proteome of reference strain SL1344. A total of 186 and 219 protein spots were recovered from Se20 and SL1344 protein extracts, respectively, after two-dimensional gel electrophoresis. The signatures of 94% of the protein spots were successfully identified through matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS). Three antimicrobial resistance related proteins, whose genes were previously detected by polymerase chain reaction (PCR), were identified in the clinical strain. The presence of these proteins, dihydropteroate synthase type-2 (sul2 gene), aminoglycoside resistance protein A (strA gene) and aminoglycoside 6'-N-acetyltransferase type Ib-cr4 (aac(6')-Ib-cr4 gene), was confirmed in the DT104B clinical strain. The aac(6')-Ib-cr4 gene is responsible for plasmid-mediated aminoglycoside and quinolone resistance. This is a preliminary analysis of the proteome of these two S. Typhimurium strains and further work is being developed to better understand how antimicrobial resistance is developing in this pathogen. PMID:25196519
Correia, Susana; Nunes-Miranda, J·lio D.; Pinto, LuĒs; Santos, Hugo M.; de Toro, MarĒa; Sßenz, Yolanda; Torres, Carmen; Capelo, Josķ Luis; Poeta, PatrĒcia; Igrejas, Gilberto
Impacts of coexisting antibiotics, antibacterial residues, and heavy metals on the occurrence of erythromycin resistance genes in urban wastewater.
Antibiotic resistance is a global challenge and represents a growing threat on human health worldwide. Wastewater treatment plants (WWTPs) are generally considered as hotspots for control and/or dissemination of antibiotic resistance. The role of antibiotics, antibacterial residues, and heavy metals played on the evolution and spread of antibiotic resistance is still not well understood. Here, the occurrence of antibiotics (i.e., macrolides, tetracyclines, sulfonamides, and quinolones), antibacterial residues (i.e., triclosan), as well as heavy metals (i.e., cadmium, chromium, copper, zinc, lead, and nickel) in urban wastewater was investigated. Also, the abundances of erythromycin resistance genes (ERY-ARGs) including ere(A), ere(B), mef(A)/mef(E), erm(A), erm(B), erm(C), and msr(A)/msr(B) genes were screened. A relationship between certain antibiotics, antibacterial residues, and heavy metals and ERY-ARGs was demonstrated. ERY presented significant correlations (0.883?
Gao, Pin; He, Shi; Huang, Shenglin; Li, Kanzhu; Liu, Zhenhong; Xue, Gang; Sun, Weimin
In vitro antibacterial effect of wasp (Vespa orientalis) venom
Background The emergence of antibacterial resistance against several classes of antibiotics is an inevitable consequence of drug overuse. As antimicrobial resistance spreads throughout the globe, new substances will always be necessary to fight against multidrug-resistant microorganisms. Venoms of many animals have recently gained attention in the search for new antimicrobials to treat infectious diseases. Thefore, the present study aimed to study the antibacterial effects of wasp (Vespa orientalis) crude venom. Two gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two gram-negative ones (Escherichia coli and Klesiella pneumonia) were compared for their sensitivity to the venom by determining the inhibition zone (Kirby-Bauer method) and minimum inhibitory concentration (MIC). A microbroth kinetic system based on continuous monitoring of changes in the optical density of bacterial growth was also used for determination of antimicrobial activity. Results The venom exhibited a well-recognized antimicrobial property against the tested bacterial strains. The inhibition zones were determined to be 12.6, 22.7, 22.4 and 10.2Āmm for S. aureus, B. subtilis, E. coli and K. pneumonia, respectively. The corresponding MIC values were determined to be 64, 8, 64 and 128Ā?g/mL, respectively. The MIC50 and MIC90 values of the venom were respectively determined to be 63.6 and 107Ā?g/mL for S. aureus, 4.3 and 7.0Ā?g/mL for B. subtilis, 45.3 and 65.7Ā?g/mL for E. coli and 74.4 and 119.2Ā?g/mL for K. pneumonia. Gram-positive bacteria were generally more sensitive to the venom than gram-negative ones. Conclusions Results revealed that the venom markedly inhibits the growth of both gram-positive and gram-negative bacteria and could be considered a potential source for developing new antibacterial drugs. PMID:24955088
Toxicity and antibacterial assessment of chitosancoated silver nanoparticles on human pathogens and macrophage cells
Background Pathogenic bacteria are able to develop various strategies to counteract the bactericidal action of antibiotics. Silver nanoparticles (AgNPs) have emerged as a potential alternative to conventional antibiotics because of their potent antimicrobial properties. The purpose of this study was to synthesize chitosan-stabilized AgNPs (CS-AgNPs) and test for their cytotoxic, genotoxic, macrophage cell uptake, antibacterial, and antibiofilm activities. Methods AgNPs were synthesized using chitosan as both a stabilizing and a reducing agent. Antibacterial activity was determined by colony-forming unit assay and scanning electron microscopy. Genotoxic and cytotoxic activity were determined by DNA fragmentation, comet, and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays. Cellular uptake and intracellular antibacterial activity were tested on macrophages. Results CS-AgNPs exhibited potent antibacterial activity against different human pathogens and also impeded bacterial biofilm formation. Scanning electron microscopy analysis indicated that CS-AgNPs kill bacteria by disrupting the cell membrane. CS-AgNPs showed no significant cytotoxic or DNA damage effect on macrophages at the bactericidal dose. Propidium iodide staining indicated active endocytosis of CS-AgNPs resulting in reduced intracellular bacterial survival in macrophages. Conclusion The present study concludes that at a specific dose, chitosan-based AgNPs kill bacteria without harming the host cells, thus representing a potential template for the design of antibacterial agents to decrease bacterial colonization and to overcome the problem of drug resistance. PMID:22619529
Jena, Prajna; Mohanty, Soumitra; Mallick, Rojee; Jacob, Biju; Sonawane, Avinash
Facile biofunctionalization of silver nanoparticles for enhanced antibacterial properties, endotoxin removal, and biofilm control
Infectious diseases cause a huge burden on healthcare systems worldwide. Pathogenic bacteria establish infection by developing antibiotic resistance and modulating the hostÆs immune system, whereas opportunistic pathogens like Pseudomonas aeruginosa adapt to adverse conditions owing to their ability to form biofilms. In the present study, silver nanoparticles were biofunctionalized with polymyxin B, an antibacterial peptide using a facile method. The biofunctionalized nanoparticles (polymyxin B-capped silver nanoparticles, PBSNPs) were assessed for antibacterial activity against multiple drug-resistant clinical strain Vibrio fluvialis and nosocomial pathogen P. aeruginosa. The results of antibacterial assay revealed that PBSNPs had an approximately 3-fold higher effect than the citrate-capped nanoparticles (CSNPs). Morphological damage to the cell membrane was followed by scanning electron microscopy, testifying PBSNPs to be more potent in controlling the bacterial growth as compared with CSNPs. The bactericidal effect of PBSNPs was further confirmed by Live/Dead staining assays. Apart from the antibacterial activity, the biofunctionalized nanoparticles were found to resist biofilm formation. Electroplating of PBSNPs onto stainless steel surgical blades retained the antibacterial activity against P. aeruginosa. Further, the affinity of polymyxin for endotoxin was exploited for its removal using PBSNPs. It was found that the prepared nanoparticles removed 97% of the endotoxin from the solution. Such multifarious uses of metal nanoparticles are an attractive means of enhancing the potency of antimicrobial agents to control infections.
Lambadi, Paramesh Ramulu; Sharma, Tarun Kumar; Kumar, Piyush; Vasnani, Priyanka; Thalluri, Sitaramanjaneya Mouli; Bisht, Neha; Pathania, Ranjana; Navani, Naveen Kumar
Facile biofunctionalization of silver nanoparticles for enhanced antibacterial properties, endotoxin removal, and biofilm control.
Infectious diseases cause a huge burden on healthcare systems worldwide. Pathogenic bacteria establish infection by developing antibiotic resistance and modulating the host's immune system, whereas opportunistic pathogens like Pseudomonas aeruginosa adapt to adverse conditions owing to their ability to form biofilms. In the present study, silver nanoparticles were biofunctionalized with polymyxin B, an antibacterial peptide using a facile method. The biofunctionalized nanoparticles (polymyxin B-capped silver nanoparticles, PBSNPs) were assessed for antibacterial activity against multiple drug-resistant clinical strain Vibrio fluvialis and nosocomial pathogen P. aeruginosa. The results of antibacterial assay revealed that PBSNPs had an approximately 3-fold higher effect than the citrate-capped nanoparticles (CSNPs). Morphological damage to the cell membrane was followed by scanning electron microscopy, testifying PBSNPs to be more potent in controlling the bacterial growth as compared with CSNPs. The bactericidal effect of PBSNPs was further confirmed by Live/Dead staining assays. Apart from the antibacterial activity, the biofunctionalized nanoparticles were found to resist biofilm formation. Electroplating of PBSNPs onto stainless steel surgical blades retained the antibacterial activity against P. aeruginosa. Further, the affinity of polymyxin for endotoxin was exploited for its removal using PBSNPs. It was found that the prepared nanoparticles removed 97% of the endotoxin from the solution. Such multifarious uses of metal nanoparticles are an attractive means of enhancing the potency of antimicrobial agents to control infections. PMID:25834431
Lambadi, Paramesh Ramulu; Sharma, Tarun Kumar; Kumar, Piyush; Vasnani, Priyanka; Thalluri, Sitaramanjaneya Mouli; Bisht, Neha; Pathania, Ranjana; Navani, Naveen Kumar
Overcoming scientific and structural bottlenecks in antibacterial discovery and development
Antibiotic resistance is becoming an increasing threat, with too few novel antibiotics coming to market to replace those lost due to resistance development. Efforts by the pharmaceutical industry to screen for and design novel antibacterials have not been successful, with several companies minimizing or closing down their antibacterial research units, leading to a loss of skills and know-how. At the same time, antibiotic innovation in academia is not filling the void due to misaligned incentive structures and lack of vital knowledge of drug discovery. The scientific and structural difficulties in discovering new antibiotics have only begun to be appreciated in the latest years. Part of the problem has been a paradigm shift within both industry and academia to focus on ærationalÆ drug development with an emphasis on single targets and high-throughput screening of large chemical libraries, which may not be suited to target bacteria. The very particular aspects of ætargeting an organism inside another organismÆ have not been given enough attention. In this paper, researcher interviews have complemented literature studies to delve deeper into the specifics of the different scientific and structural barriers, and some potential solutions are offered. PMID:24646118
Evaluation of Madurahydroxylactone as a Slow Release Antibacterial Implant Coating
Madurahydroxylactone (MHL), a secondary metabolite with antibacterial activity was evaluated for its suitability to generate controlled drug release coatings on medical implant materials. A smooth and firmly attached layer could be produced from a precursor solution on various metallic implant materials. In physiological salt solutions these coatings dissolved within a time period up to one week. A combination of MHL with a broad spectrum fluoroquinolone antibiotic was used to create a coating that was active against all bacterial strains tested. The time period during which the coating remained active against Pseudomonas aeruginosa was investigated. The results indicated a delayed drug release from single layer coatings in the course of seven days. MHL was biocompatible in cell culture assays and could after a delay even serve as a cell adhesion substrate for human or murine cells. The findings indicate a potential for MHL for the generation of delayed release antimicrobial implant coatings. PMID:21625377
Badar, Muhammad; Hemmen, Katherina; Nimtz, Manfred; Stieve, Martin; Stiesch, Meike; Lenarz, Thomas; Hauser, Hansj÷rg; M÷llmann, Ute; Vogt, Sebastian; Schnabelrauch, Matthias; Mueller, Peter P
Validation of a MLC method with fluorescence detection for the determination of quinolones in urine samples by direct injection
A sensitive and robust method was developed and validated for the routine identification and quantification of five quinolones in urine samples directly injected into a micellar liquid chromatographic system without any pre-treatment step. Since the simultaneous elution of the five compounds was not resolved, two mobile phases have been proposed: (a) for ciprofloxacin and levofloxacin 0.15M sodium dodecyl sulphate, 12.5%
Maria Rambla-Alegre; Josep Esteve-Romero; Samuel Carda-Broch
Simultaneous Separation and Determination of Seven Quinolones Using HPLC: Analysis of Levofloxacin and Moxifloxacin in Plasma and Amniotic Fluid
A reversed-phase high-performance liquid chromatographic method is described for the determination of seven quinolones in\\u000a plasma and amniotic fluid. Experimental designs have been applied for the optimization of the method in order to determine\\u000a the experimental conditions for maximized resolution and minimized retention time. A total desirability function D that weights the responses together was used to optimize the two
E. Nemutlu; S. K?r; ų. ųzy³nc³; M. S. Beksań
Mutations in Topoisomerase IV and DNA Gyrase of Staphylococcus aureus: Novel Pleiotropic Effects on Quinolone and Coumarin Activity
Previous studies have shown that topoisomerase IV and DNA gyrase interact with quinolones and coumarins in different ways. The MICs of coumarins (novobiocin and coumermycin) for MT5, a Staphylococcus aureus nov mutant, are higher than those for wild-type strains. Sequencing the gyrB gene encoding one subunit of the DNA gyrase revealed the presence of a double mutation likely to be
Differences between Two New Quinolones (Gemifloxacin and Trovafloxacin) and Ciprofloxacin in Their Concentration-Dependent Killing of Streptococcus pneumoniae
Background: Ciprofloxacin resistance influences the in vitro effect of new quinolones on Streptococcus pneumoniae.Methods: The early (over 3 h) in vitro bactericidal activity of gemifloxacin, trovafloxacin and ciprofloxacin was explored by time-kill tests against two ciprofloxacin-susceptible (MIC = 0.5 and 1 ?g\\/ml) and two ciprofloxacin-resistant (MIC = 16 ?g\\/ml) S. pneumoniae strains. Results: At subinhibitory concentrations (0.5 ū MIC) and
P. Joyanes; A. Pascual; M. J. Gimķnez; I. GarcĒa; L. Aguilar; E. Perea
Enterobacteriaceae resistant to third-generation cephalosporins and quinolones in fresh culinary herbs imported from Southeast Asia.
Since multidrug resistant bacteria are frequently reported from Southeast Asia, our study focused on the occurrence of ESBL-producing Enterobacteriaceae in fresh imported herbs from Thailand, Vietnam and Malaysia. Samples were collected from fresh culinary herbs imported from Southeast Asia in which ESBL-suspected isolates were obtained by selective culturing. Analysis included identification by MALDI-TOF mass spectrometry, susceptibility testing, XbaI-PFGE, microarray, PCR and sequencing of specific ESBL genes, PCR based replicon typing (PBRT) of plasmids and Southern blot hybridization. In addition, the quinolone resistance genotype was characterized by screening for plasmid mediated quinolone resistance (PMQR) genes and mutations in the quinolone resistance determining region (QRDR) of gyrA and parC. The study encompassed fifty samples of ten batches of culinary herbs (5 samples per batch) comprising nine different herb variants. The herbs originated from Thailand (Water morning glory, Acacia and Betel leaf), Vietnam (Parsley, Asian pennywort, Houttuynia leaf and Mint) and Malaysia (Holy basil and Parsley). By selective culturing 21 cefotaxime resistant Enterobacteriaceae were retrieved. Array analysis revealed 18 isolates with ESBL genes and one isolate with solely non-ESBL beta-lactamase genes. Mutations in the ampC promoter region were determined in two isolates with PCR and sequencing. The isolates were identified as Klebsiella pneumoniae (n=9), Escherichia coli (n=6), Enterobacter cloacae complex (n=5) and Enterobacter spp. (n=1). All isolates tested were multidrug resistant. Variants of CTX-M enzymes were predominantly found followed by SHV enzymes. PMQR genes (including aac(6')-1b-cr, qnrB and qnrS) were also frequently detected. In almost all cases ESBL and quinolone resistance genes were located on the same plasmid. Imported fresh culinary herbs from Southeast Asia are a potential source for contamination of food with multidrug resistant bacteria. Because these herbs are consumed without appropriate heating, transfer to human bacteria cannot be excluded. PMID:24607424
Veldman, Kees; Kant, Arie; Dierikx, Cindy; van Essen-Zandbergen, Alieda; Wit, Ben; Mevius, Dik
Alterations in Topoisomerase IV and DNA Gyrase in Quinolone- Resistant Mutants of Mycoplasma hominis Obtained In Vitro
Mycoplasma hominis mutants were selected stepwise for resistance to ofloxacin and sparfloxacin, and their gyrA, gyrB, parC, and parE quinolone resistance-determining regions were characterized. For ofloxacin, four rounds of selection yielded six first-, six second-, five third-, and two fourth-step mutants. The first-step mu- tants harbored a single Asp4263Asn substitution in ParE. GyrA changes (Ser833Leu or Trp) were found only
Stimuli-responsive self-assembling peptides made from antibacterial peptides
NASA Astrophysics Data System (ADS)
How to use bioactive peptide sequences as fundamental building blocks to make hydrogel materials which are stimuli-responsive? In this article, we provide a novel designed peptide comprising two antibacterial peptide sequences (KIGAKI)3-NH2 and a central tetrapeptide linker. Results show that balancing the forces of the electrostatic repulsion of the charged lysine residues against the hydrophobic collapse of the isoleucine and alanine residues and backbone ?-sheet hydrogen bonding allows the structural transition and formation of individually dispersed nanofibers. Circular Dichroism (CD) and rheology analysis demonstrated that the designed peptide can undergo an abrupt structural transition from a random coil to a stable unimolecular ?-hairpin conformation and subsequently form an elastic hydrogel when exposed to external stimuli such as pH, ionic strength and heat. The assembly kinetics of the obtained antibacterial sequence comprising peptide (ASCP) was studied by time-lapse Atomic Force Microscopy (AFM) and Thioflavin T (ThT) binding assay. In addition, the inherent antibacterial activity of the peptide hydrogel was confirmed by the antibacterial assay against Escherichia coli. This example described epitomizes the use of bioactive peptide sequences in the design of finite self-assembled structures with potential inherent activity. These hydrogel materials may find applications in drug delivery, tissue engineering and regenerative medicine.How to use bioactive peptide sequences as fundamental building blocks to make hydrogel materials which are stimuli-responsive? In this article, we provide a novel designed peptide comprising two antibacterial peptide sequences (KIGAKI)3-NH2 and a central tetrapeptide linker. Results show that balancing the forces of the electrostatic repulsion of the charged lysine residues against the hydrophobic collapse of the isoleucine and alanine residues and backbone ?-sheet hydrogen bonding allows the structural transition and formation of individually dispersed nanofibers. Circular Dichroism (CD) and rheology analysis demonstrated that the designed peptide can undergo an abrupt structural transition from a random coil to a stable unimolecular ?-hairpin conformation and subsequently form an elastic hydrogel when exposed to external stimuli such as pH, ionic strength and heat. The assembly kinetics of the obtained antibacterial sequence comprising peptide (ASCP) was studied by time-lapse Atomic Force Microscopy (AFM) and Thioflavin T (ThT) binding assay. In addition, the inherent antibacterial activity of the peptide hydrogel was confirmed by the antibacterial assay against Escherichia coli. This example described epitomizes the use of bioactive peptide sequences in the design of finite self-assembled structures with potential inherent activity. These hydrogel materials may find applications in drug delivery, tissue engineering and regenerative medicine. Electronic supplementary information (ESI) available: Fig. S1-S5. See DOI: 10.1039/c3nr00225j
Liu, Yanfei; Yang, Yanlian; Wang, Chen; Zhao, Xiaojun
High Resolution Melting Analysis for Rapid Mutation Screening in Gyrase and Topoisomerase IV Genes in Quinolone-Resistant Salmonella enterica
The increased Salmonella resistance to quinolones and fluoroquinolones is a public health concern in the Southeast Asian region. The objective of this study is to develop a high resolution melt curve (HRM) assay to rapidly screen for mutations in quinolone-resistant determining region (QRDR) of gyrase and topoisomerase IV genes. DNA sequencing was performed on 62 Salmonella strains to identify mutations in the QRDR of gyrA, gyrB, parC, and parE genes. Mutations were detected in QRDR of gyrA (n = 52; S83F, S83Y, S83I, D87G, D87Y, and D87N) and parE (n = 1; M438I). Salmonella strains with mutations within QRDR of gyrA are generally more resistant to nalidixic acid (MIC 16 > 256??g/mL). Mutations were uncommon within the QRDR of gyrB, parC, and parE genes. In the HRM assay, mutants can be distinguished from the wild-type strains based on the transition of melt curves, which is more prominent when the profiles are displayed in difference plot. In conclusion, HRM analysis allows for rapid screening for mutations at the QRDRs of gyrase and topoisomerase IV genes in Salmonella. This assay markedly reduced the sequencing effort involved in mutational studies of quinolone-resistance genes. PMID:25371903
Thong, Kwai Lin
Nail disorders are defined according to their appearance and the part of the nail affected: the nail plate, the tissues that support or hold the nail plate in place, or the lunula. The consequences of most nail disorders are purely cosmetic. Other disorders, such as ingrown nails, inflammation, erythema, abscesses or tumours, cause functional impairment or pain. The appearance of the lesions is rarely indicative of their cause. Possible causes include physiological changes, local disorders or trauma, systemic conditions, toxic substances and drugs. Most drug-induced nail disorders resolve after discontinuation of the drug, although complete resolution sometimes takes several years. Drugs appear to induce nail disorders through a variety of mechanisms. Some drugs affect the nail matrix epithelium, the nail bed or the nail folds. Some alter nail colour. Other drugs induce photosensitivity. Yet others affect the blood supply to the nail unit. Nail abnormalities are common during treatment with certain cytotoxic drugs: taxanes, anthracyclines, fluorouracil, EGFR, tyrosine kinase inhibitors, etc. Some drugs are associated with a risk of serious and painful lesions, such as abscesses. When these disorders affect quality of life, the benefits of withdrawing the drug must be weighed against the severity of the condition being treated and the drug's efficacy, taking into account the harm-benefit balance of other options. Various anti-infective drugs, including tetracyclines, quinolones, clofazimine and zidovudine, cause the nail plate to detach from the nail bed after exposure to light, or cause nail discoloration. Psoralens and retinoids can also have the same effects. PMID:25162091
In vitro Evaluation of Ro 23¢6240, a New Fluorinated 4-Quinolone
The in vitro antibacterial activity of Ro 23¢6240 was assessed and compared with those of ciprofloxacin and beta-lactam antibiotics including several oral compounds against members of the family Enterobacteriaceae (n = 130) and Pseudomonas spp. (n = 31). In general, Ro 23¢6240 was 2 dilution steps less active than ciprofloxacin. For the Pseudomonas spp. the MICs for 90% inhibition were
Ellen E. Stobberingh; Anthony W. Houben; Cees P. A. van Boven
drug discovery at Purdue #12;drug discovery 2 #12;drug discovery 3 Introduction The drug discovery and innovative drug candidates to treat chronic and acute illnesses. Our researchers also continue to be invested in various approaches to drug discovery, which include understanding of drug targets for future drug
A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore.
As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity. PMID:19164768
Miller, J Richard; Dunham, Steve; Mochalkin, Igor; Banotai, Craig; Bowman, Matthew; Buist, Susan; Dunkle, Bill; Hanna, Debra; Harwood, H James; Huband, Michael D; Karnovsky, Alla; Kuhn, Michael; Limberakis, Chris; Liu, Jia Y; Mehrens, Shawn; Mueller, W Thomas; Narasimhan, Lakshmi; Ogden, Adam; Ohren, Jeff; Prasad, J V N Vara; Shelly, John A; Skerlos, Laura; Sulavik, Mark; Thomas, V Hayden; VanderRoest, Steve; Wang, LiAnn; Wang, Zhigang; Whitton, Amy; Zhu, Tong; Stover, C Kendall
A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore
As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious Gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.
Miller, J. Richard; Dunham, Steve; Mochalkin, Igor; Banotai, Craig; Bowman, Matthew; Buist, Susan; Dunkle, Bill; Hanna, Debra; Harwood, H. James; Huband, Michael D.; Karnovsky, Alla; Kuhn, Michael; Limberakis, Chris; Liu, Jia Y.; Mehrens, Shawn; Mueller, W. Thomas; Narasimhan, Lakshmi; Ogden, Adam; Ohren, Jeff; Prasad, J.V.N. Vara; Shelly, John A.; Skerlos, Laura; Sulavik, Mark; Thomas, V. Hayden; VanderRoest, Steve; Wang, LiAnn; Wang, Zhigang; Whitton, Amy; Zhu, Tong; Stover, C. Kendall; (Pfizer)
The antibacterial activity of hexamine (methenamine), hexamine hippurate and hexamine mandelate
Summary The antibacterial activity of hexamine and two of its organic acid salts was compared by continuous turbidimetric monitoring of static cultures exposed to the drugs and in anin vitro model of the treatment of bacterial cystitis. At pH 5.5, concentrations of 32 to 125 mg hexamine per 1 caused some inhibition of bacterial growth, but 250 to 500 mg\\/l
D. Greenwood; R. C. B. Slack
Conformational analysis of a quinolonic ribonucleoside with anti-HSV-1 activity
NASA Astrophysics Data System (ADS)
The infections caused by the Herpes Simplex Virus are one of the most common sources of diseases in adults and several natural nucleoside analogues are currently used in the treatment of these infections. In vitro tests of a series of quinolonic ribonucleosides derivatives synthesized by part of our group indicated that some of them have antiviral activity against HSV-1. The conformational analysis of bioactive compounds is extremely important in order to better understand their chemical structures and biological activity. In this work, we have carried out a nuclear relaxation NMR study of 6-Me ribonucleoside derivative in order to determine if the syn or anti conformation is preferential. The NMR analysis permits the determination of inter-atomic distances by using techniques which are based on nuclear relaxation and related phenomena. Those techniques are non-selective longitudinal or spin-lattice relaxation rates and NULL pulse sequence, which allow the determination of distances between pairs of hydrogen atoms. The results of NMR studies were compared with those obtained by molecular modeling.
Yoneda, Julliane D.; Velloso, Marcia Helena R.; Leal, Kßtia Z.; Azeredo, Rodrigo B. de V.; Sugiura, Makiko; Albuquerque, Magaly G.; Santos, Fernanda da C.; Souza, Maria CecĒlia B. V. de; Cunha, Anna Claudia; Seidl, Peter R.; Alencastro, Ricardo B. de; Ferreira, Vitor F.
The Pseudomonas Quinolone Signal (PQS) Balances Life and Death in Pseudomonas aeruginosa Populations
When environmental conditions deteriorate and become inhospitable, generic survival strategies for populations of bacteria may be to enter a dormant state that slows down metabolism, to develop a general tolerance to hostile parameters that characterize the habitat, and to impose a regime to eliminate damaged members. Here, we provide evidence that the pseudomonas quinolone signal (PQS) mediates induction of all of these phenotypes. For individual cells, PQS, an interbacterial signaling molecule of Pseudomonas aeruginosa, has both deleterious and beneficial activities: on the one hand, it acts as a pro-oxidant and sensitizes the bacteria towards oxidative and other stresses and, on the other, it efficiently induces a protective anti-oxidative stress response. We propose that this dual function fragments populations into less and more stress tolerant members which respond differentially to developing stresses in deteriorating habitats. This suggests that a little poison may be generically beneficial to populations, in promoting survival of the fittest, and in contributing to bacterial multi-cellular behavior. It further identifies PQS as an essential mediator of the shaping of the population structure of Pseudomonas and of its response to and survival in hostile environmental conditions. PMID:18818733
Hõussler, Susanne; Becker, Tanja
Tandem prenyltransferases catalyze isoprenoid elongation and complexity generation in biosynthesis of quinolone alkaloids.
Modification of natural products with prenyl groups and the ensuing oxidative transformations are important for introducing structural complexity and biological activities. Penigequinolones (1) are potent insecticidal alkaloids that contain a highly modified 10-carbon prenyl group. Here we reveal an iterative prenylation mechanism for installing the 10-carbon unit using two aromatic prenyltransferases (PenI and PenG) present in the gene cluster of 1 from Penicillium thymicola. The initial Friedel-Crafts alkylation is catalyzed by PenI to yield dimethylallyl quinolone 6. The five-carbon side chain is then dehydrogenated by a flavin-dependent monooxygenase to give aryl diene 9, which serves as the electron-rich substrate for a second alkylation with dimethylallyl diphosphate to yield stryrenyl product 10. The completed, oxidized 10-carbon prenyl group then undergoes further structural morphing to yield yaequinolone C (12), the immediate precursor of 1. Our studies have therefore uncovered an unprecedented prenyl chain extension mechanism in natural product biosynthesis. PMID:25859931
Zou, Yi; Zhan, Zhajun; Li, Dehai; Tang, Mancheng; Cacho, Ralph A; Watanabe, Kenji; Tang, Yi
Technology Transfer Automated Retrieval System (TEKTRAN)
A modification of "AATCC Test Method 100-1999, Antibacterial Finishes on Textile Materials: Assessment of," was used for assaying the antibacterial properties of denim containing various flax levels. When the effect of drying was looked at, increased flax content did not improve the rate of drying ...
Antibacterial activity against Porphyromonas gingivalis and biological characteristics of antibacterial stainless steel.
To evaluate the possibility of an alternative to the traditional orthodontic stainless steel implants, the antibacterial activity against Porphyromonas gingivalis (P. gingivalis) and the related cytotoxicity of a type 304 Cu bearing antibacterial stainless steel were studied. The results indicated that the antibacterial stainless steel showed excellent antibacterial property against P. gingivalis, compared with the control steel (a purchased medical grade 304 stainless steel). Compared to the control steel, there were fewer bacteria on the surface of the antibacterial stainless steel, with significant difference in morphology. The cytotoxicities of the antibacterial stainless steel to both MG-63 and KB cells were all grade 1, the same as those of the control steel. There were no significant differences in the apoptosis rates on MG-63 and KB cells between the antibacterial stainless steel and the control steel. This study demonstrates that the antibacterial stainless steel is possible to reduce the incidence of implant-related infections and can be a more suitable material for the micro-implant than the conventional stainless steel in orthodontic treatment. PMID:23352947
Zhang, Dan; Ren, Ling; Zhang, Yang; Xue, Nan; Yang, Ke; Zhong, Ming
A general ANN-based multitasking model for the discovery of potent and safer antibacterial agents.
Bacteria have been one of the world's most dangerous and deadliest pathogens for mankind, nowadays giving rise to significant public health concerns. Given the prevalence of these microbial pathogens and their increasing resistance to existing antibiotics, there is a pressing need for new antibacterial drugs. However, development of a successful drug is a complex, costly, and time-consuming process. Quantitative Structure-Activity Relationships (QSAR)-based approaches are valuable tools for shortening the time of lead compound identification but also for focusing and limiting time-costly synthetic activities and in vitro/vivo evaluations. QSAR-based approaches, supported by powerful statistical techniques such as artificial neural networks (ANNs), have evolved to the point of integrating dissimilar types of chemical and biological data. This chapter reports an overview of the current research and potential applications of QSAR modeling tools toward the rational design of more efficient antibacterial agents. Particular emphasis is given to the setup of multitasking models along with ANNs aimed at jointly predicting different antibacterial activities and safety profiles of drugs/chemicals under diverse experimental conditions. PMID:25502375
Speck-Planche, A; Cordeiro, M N D S
A high-throughput screen identifies a new natural product with broad-spectrum antibacterial activity.
Due to the inexorable invasion of our hospitals and communities by drug-resistant bacteria, there is a pressing need for novel antibacterial agents. Here we report the development of a sensitive and robust but low-tech and inexpensive high-throughput metabolic screen for novel antibiotics. This screen is based on a colorimetric assay of pH that identifies inhibitors of bacterial sugar fermentation. After validation of the method, we screened over 39,000 crude extracts derived from organisms that grow in the diverse ecosystems of Costa Rica and identified 49 with reproducible antibacterial effects. An extract from an endophytic fungus was further characterized, and this led to the discovery of three novel natural products. One of these, which we named mirandamycin, has broad-spectrum antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae, methicillin-resistant Staphylococcus aureus, and Mycobacterium tuberculosis. This demonstrates the power of simple high throughput screens for rapid identification of new antibacterial agents from environmental samples. PMID:22359585
Ymele-Leki, Patrick; Cao, Shugeng; Sharp, Jared; Lambert, Kathleen G; McAdam, Alexander J; Husson, Robert N; Tamayo, Giselle; Clardy, Jon; Watnick, Paula I
Synthesis, characterization and antibacterial properties of dihydroxy quaternary ammonium salts with long chain alkyl bromides.
Five N-methyl-N-R-N,N-bis(2-hydroxyethyl) ammonium bromides (R = -benzyl (chloride, BNQAS), -dodecyl (C12QAS), -tetradecyl (C14QAS), -hexadecyl (C16QAS), -octadecyl (C18QAS)) were prepared based on N-methyldiethanolamine (MDEA) and halohydrocarbon. Five QAS were characterized by FTIR, NMR, and MS. BNQAS, C12QAS, C14QAS, and C16QAS were confirmed by X-ray single-crystal diffraction. Their antibacterial properties indicated good antibacterial abilities against E. coli, S. aureus, B. subtilis, especially C12QAS with the best antibacterial ability (100% to E. coli, 95.65% to S. aureus, and 91.41% to B. subtilis). In addition, C12QAS also displayed the best antifungal activities than BNQAS and C18QAS against Cytospora mandshurica, Botryosphaeria ribis, Physalospora piricola, and Glomerella cingulata with the ratio of full marks. The strategy provides a facile way to design and develop new types of antibacterial drugs for application in preventing the fruit rot, especially apple. PMID:25215430
Liu, Wen-Shuai; Wang, Chun-Hua; Sun, Ju-Feng; Hou, Gui-Ge; Wang, Yu-Peng; Qu, Rong-Jun
In vitro antibacterial activity of Hibiscus rosa-sinensis flower extract against human pathogens
Objective To access the in vitro antibacterial activity of Hibiscus rosa-sinensis (H. rosa- sinensis) flower extract against human pathogens. Methods Antibacterial activity was evaluated by using disc and agar diffusion methods. The protein was run through poly acrylmide gel electrophoresis to view their protein profile. Results The results showed that the cold extraction illustrates a maximum zone of inhibition against Bacillus subtillis (B. subtillis), Escherichia coli (E. coli) viz., (17.00 ▒ 2.91), (14.50 ▒ 1.71) mm, followed by hot extraction against, E. coli, Salmonella sp. as (11.66 ▒ 3.14), (10.60 ▒ 3.09) mm. In methanol extraction showed a highest zone of inhibition recorded against B. subtillis, E. coli as (18.86 ▒ 0.18), (18.00 ▒ 1.63) mm pursued by ethanol extraction showed utmost zone of inhibition recorded against Salmonella sp. at (20.40 ▒ 1.54) mm. The crude protein from flower showed a maximum inhibitory zone observed against Salmonella sp., E. coli viz., (16.55 ▒ 1.16), (14.30 ▒ 2.86) mm. The flower material can be taken as an alternative source of antibacterial agent against the human pathogens. Conclusions The extracts of the H. rosa-sinensis are proved to have potential antibacterial activity, further studies are highly need for the drug development. PMID:23569938
Ruban, P; Gajalakshmi, K
A High-Throughput Screen Identifies a New Natural Product with Broad-Spectrum Antibacterial Activity
Due to the inexorable invasion of our hospitals and communities by drug-resistant bacteria, there is a pressing need for novel antibacterial agents. Here we report the development of a sensitive and robust but low-tech and inexpensive high-throughput metabolic screen for novel antibiotics. This screen is based on a colorimetric assay of pH that identifies inhibitors of bacterial sugar fermentation. After validation of the method, we screened over 39,000 crude extracts derived from organisms that grow in the diverse ecosystems of Costa Rica and identified 49 with reproducible antibacterial effects. An extract from an endophytic fungus was further characterized, and this led to the discovery of three novel natural products. One of these, which we named mirandamycin, has broad-spectrum antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae, methicillin-resistant Staphylococcus aureus, and Mycobacterium tuberculosis. This demonstrates the power of simple high throughput screens for rapid identification of new antibacterial agents from environmental samples. PMID:22359585
Ymele-Leki, Patrick; Cao, Shugeng; Sharp, Jared; Lambert, Kathleen G.; McAdam, Alexander J.; Husson, Robert N.; Tamayo, Giselle; Clardy, Jon; Watnick, Paula I.
Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids
Summary A chemical library of carboxamide-substituted tetramates designed by analogy with antibacterial natural products, a method for their rapid construction, and the evaluation of their antibacterial activity is reported. PMID:24204399
Jeong, Yong-Chul
Genetics and regulation of outer membrane protein expression by quinolone resistance loci nfxB, nfxC, and cfxB.
Quinolone resistance mutations (cfxB1, marA1, and soxQ1) that reduce porin outer membrane protein OmpF map near 34 min on the Escherichia coli chromosome. Another such mutation, nfxC1, was found in strain KF131 (nfxB, 19 min). nfxC1 and cfxB1 mutants (selected with quinolones) differed slightly but reproducibly from marA1 (selected with tetracycline) and soxQ1 (selected with menadione) mutants in quinolone resistance and linkage to zdd2208::Tn10kan (33.7 min). For nfxB nfxC1 and cfxB1 mutants, as previously shown for marA mutants, resistance and reduced OmpF required the micF locus encoding an antisense RNA complementary to ompF mRNA and were associated with increased micF expression. Images PMID:1510409
Hooper, D C; Wolfson, J S; Bozza, M A; Ng, E Y
Antibacterial diterpenoids from Sagittaria pygmaea.
There were five new diterpenoids, 18-beta-D-3',4'-diacetoxyxylopyranosyl-ent-kaur-16-ene (1), 18-beta-L-3',5'-diacetoxyarabinofuranosyl-ent-kaur-16-ene (2), 18-beta-D-3',6'-diacetoxyglucopyranosyl-ent-kaur-16-ene (3), ent-isopimar-8(14),15-dien-19-oic acid (4), and 5alpha-hydroxy-ent-rosa-15-en-18-oic acid (5), isolated from the whole herb of Sagittaria pygmaea. Their structures and relative configurations were established based on spectroscopic studies, chemical methods, and X-ray crystallographic analysis. Compound 2 exhibited significant antibacterial activity against the oral pathogens, Streptococcus mutans ATCC 25 175 and Actinomyces viscosus ATCC 27 044, with MIC values against both pathogens of 15.6 microg/mL. Compound 3 was active against only A. viscosus ATCC 27 044 with an MIC value of 62.5 microg/mL. Compounds 4 and 5 were active against S. mutans ATCC 25 175 and A. viscosus ATCC 27 044, with MIC values against both pathogens of 125.0 microg/mL. PMID:17315313
Liu, Xue-Ting; Shi, Yao; Yu, Biao; Williams, Ian D; Sung, Herman H Y; Zhang, Qiong; Liang, Jing-Yu; Ip, Nancy Y; Min, Zhi-Da
76 FR 59406 - Anti-Infective Drugs Advisory Committee; Notice of Meeting
Federal Register 2010, 2011, 2012, 2013, 2014
...antibacterials for the treatment of community-acquired bacterial pneumonia and the draft document entitled ``Guidance for Industry: Community-Acquired Bacterial Pneumonia: Developing Drugs for Treatment,'' published March 2009...
A new antibacterial titanium-copper sintered alloy: preparation and antibacterial property.
Copper element was added in pure titanium by a powder metallurgy to produce a new antibacterial titanium-copper alloy (Ti-Cu alloy). This paper reported the very early stage results, emphasizing on the preparation, mechanical property and antibacterial activity. The phase constitution was analyzed by XRD and the microstructure was observed under SEM equipped with EDS. The hardness, the compressive strength and the corrosion resistance of Ti-Cu alloy were tested in comparison with cp-Ti. The antibacterial property of the Ti-Cu alloy was assessed by two methods: agar diffusion assay and plate-count method, in which Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) were used. XRD and SEM results showed that Ti2Cu phase and Cu-rich phase were synthesized in the Ti-Cu sintered alloy, which significantly increases the hardness and the compressive strength compared with cp-Ti and slightly improves the corrosion resistance. No antibacterial activity was detected by the agar diffusion assay on the Ti-Cu alloy, but the plate-count results indicated that the Ti-Cu alloy exhibited strong antibacterial property against both bacteria even after three polishing treatments, which demonstrates strongly that the whole alloy is of antibacterial activity. The antibacterial mechanism was thought to be in associated with the Cu ion released from the Ti-Cu alloy. PMID:23910344
Zhang, Erlin; Li, Fangbing; Wang, Hongying; Liu, Jie; Wang, Chunmin; Li, Muqin; Yang, Ke
A Comparison between Antibacterial Activity of Propolis and Aloe vera on Enterococcus faecalis (an In Vitro Study).
Removing the bacteria, including Enterococcus faecalis, from the root canal is one of the important aims in endodontic treatment.We aimed to compare the antibacterial activity of Chlorhexidine with two natural drugs. The antibacterial activities of three different propolis extracts (alcohol concentrations: 0, 15, 40%) and Aloe vera gel on E. faecalis were compared using three methods: disk diffusion, microdilution and direct contact test. In addition to the above bacterium, the Aloe vera gel effect on Staphylococcus aureus and Streptococcus mutans was evaluated. Disk diffusion test revealed that propolis ethanolic extracts (the alcohol concentration of 15 and 40%) and Aloe vera gel have antibacterial activities but aqueous extract of propolis did not show any effect in this test. The MICs for propolis ethanolic extracts, Aloe vera gel and aqueous extract of propolis (0% alcohol) were 313 Ąg/ml, 750 Ąg/ml, 2250 Ąg/ml, and ? 500 Ąg/ml respectively, much higher than the Chlorhexidine one. In direct contact test, contrary to Aloe vera, all three propolis extracts showed antibacterial effects on E. faecalis. The Aloe vera gel also showed significant antibacterial effect on S.aureus and S.mutans. The hydroalcoholic extracts of propolis and Aloe vera gel had antibacterial effects on E. faecalis, however, propolis is more potent than Aloe vera. The antibacterial effect of Aloe vera on S. aureus and S. mutans is low (MIC ? 2250 Ąg/ml). Appropriate concentrations of alcoholic extracts of propolis and some fractions of Aloe vera gel might be good choices for disinfecting the root canal in endodontic treatments. PMID:24551800
Ehsani, Maryam; Amin Marashi, Mahmood; Zabihi, Ebrahim; Issazadeh, Maryam; Khafri, Soraya
Synthesis, spectral features and biological activity of some novel hetarylazo dyes derived from 8-chloro-4-hydroxyl-2-quinolone
NASA Astrophysics Data System (ADS)
In this study, 8-chloro-4-hydroxyl-2-quinolone was synthesized from cyclocondensation of corresponding dianilide and subsequently used as a potent coupling component with some diazotized heterocyclic amines. These compounds were characterized by UV-vis, FT-IR, 1H NMR spectroscopic techniques and elemental analysis. Absorption spectra of these dyes were measured in six polar solvents and discussed with respect to the nature of solvents and substituted groups. The effects of acid, base, temperature and concentration on the visible absorption spectra of the dyes were reported. In addition, the antimicrobial activity of the dyes was explored in detail.
Yahyazadeh, Asieh; Yousefi, Hessamoddin
The influence of a newly developed quinolone: antofloxacin, on CYP activity in rats.
To investigate a newly developed quinolone antibiotics, the effect of antofloxacin hydrochloride on cytochrome P450 isoforms in rats was examined. A cocktail approach was adopted. Theophylline (CYP1A2), midazolam (CYP3A), chlorzoxazone (CYP2E1), dextromethorphan (CYP2D6), omeprazole (CYP2C19) and diclofenac (CYP2C9) were used as probes in the study, and own control was adopted. In Protocol 1, probes were given to rats simultaneously by co-administration with antofloxacin. The blood samples were obtained at designated time, and plasma concentrations of the six probes were determined by LC-MS. The pharmacokinetic parameters were calculated and compared in experimental groups in the absence and presence of antofloxacin. The result showed that the presence of antofloxacin resulted in a significant increase in theophylline values of AUC0-T and t1/2 (PAUC0-T = 0.0004 vs control Pt1/2 = 0.005 vs control), indicating that antofloxacin delayed the clearance of theophylline. In Protocol 2, the probes' pharmacokinetic parameters were compared in rats that received six probes before and after 14.5 days of consecutive administration of antofloxacin (15 mg x kg(-1), given orally, twice daily). The results suggested that the AUC0-T of chlorzoxazone was significantly decreased (P = 0.024), while that of dextromethorphan was significantly increased (P = 0.027). In conclusion, these results indicated that antofloxacin may inhibit the activity of CYP1A2, thus delaying the clearance of its substrates, and may have a slight inhibitory effect on CYP2D6 as well as an inductive effect on CYP2E1 following chronic administration. PMID:18543578
Xu, Xiao; Liu, Hai-Yan; Liu, Li; Xie, Lin; Liu, Xiao-Dong
Natural Products and Drug Discovery
For more than 50 yr, natural products have served us well in combating infectious bacteria and fungi. During the 20th century,\\u000a microbial and plant secondary metabolites helped to double our life span, reduced pain and suffering, and revolutionized medicine.\\u000a The increased development of resistance to older antibacterial, antifungal, and antitumor drugs has been challenged by (1) newly discovered antibiotics (e.g.,
Arnold L. Demain; Lixin Zhang
Injectable Bioadhesive Hydrogels with Innate Antibacterial Properties
Surgical site infections cause significant postoperative morbidity and increased healthcare costs. Bioadhesives used to fill surgical voids and support wound healing are typically devoid of antibacterial activity. Here, we report novel syringe-injectable bioadhesive hydrogels with inherent antibacterial properties prepared from mixing polydextran aldehyde (PDA) and branched polyethylenimine (PEI). These adhesives kill both Gram-negative and Gram¢positive bacteria, while sparing human erythrocytes. An optimal composition of 2.5 wt % oxidized dextran and 6.9 wt % PEI sets within seconds forming a mechanically rigid (~1700 Pa) gel offering a maximum adhesive stress of ~ 2.8 kPa. A murine infection model showed that the adhesive is capable of killing S. pyogenes introduced subcutaneously at the bioadhesiveÆs surface, with minimal inflammatory response. The adhesive was also effective in a cecal ligation and puncture model, preventing sepsis and significantly improving survival. These bioadhesives represent novel, inherently antibacterial materials for wound filling applications. PMID:24958189
Giano, Michael C.; Ibrahim, Zuhaib; Medina, Scott H.; Sarhane, Karim A.; Christensen, Joani M.; Yamada, Yuji; Brandacher, Gerald; Schneider, Joel P.
Targeting Antibacterial Agents by Using Drug-Carrying Filamentous Bacteriophages
Bacteriophages have been used for more than a century for (unconventional) therapy of bacterial infections, for half a century as tools in genetic research, for 2 decades as tools for discovery of specific target-binding proteins, and for nearly a decade as tools for vaccination or as gene delivery vehicles. Here we present a novel application of filamentous bacteriophages (phages) as
Iftach Yacoby; Marina Shamis; Hagit Bar; Doron Shabat; Itai Benhar
Improved antibacterial activity and biocompatibility on vancomycin-loaded TiO2 nanotubes: in vivo and in vitro studies
The goal for current orthopedic implant research is to design implants that have not only good biocompatibility but also antibacterial properties. TiO2 nanotubes (NTs) were fabricated on the titanium surface through electrochemical anodization, which added new properties, such as enhanced biocompatibility and potential utility as drug nanoreservoirs. The aim of the present study was to investigate the antibacterial properties and biocompatibility of NTs loaded with vancomycin (NT-V), both in vitro and in vivo. Staphylococcus aureus was used to study the antibacterial properties of the NT-V. There were three study groups: the commercially pure titanium (Cp-Ti) group, the NT group (nonloaded vancomycin), and the NT-V group. We compared NT-V biocompatibility and antibacterial efficacy with those of the NT and Cp-Ti groups. Compared with Cp-Ti, NT-V showed good antibacterial effect both in vitro and in vivo. Although the NTs reduced the surface bacterial adhesion in vitro, implant infection still developed in in vivo studies. Furthermore, the results also revealed that both NTs and NT-V showed good biocompatibility. Therefore, the NTs loaded with antibiotic might be potentially used for future orthopedic implants. PMID:24403827
Zhang, Hangzhou; Sun, Yu; Tian, Ang; Xue, Xiang Xin; Wang, Lin; Alquhali, Ali; Bai, Xizhuang
[Infectious diseases caused by carbapenemase-producing Enterobacteriaceae--a particular challenge for antibacterial therapy].
Enterobacteriaceae species such as Escherichia coli and Klebsiella pneumoniae are among the most common human pathogens. They are responsible for a wide range of community-acquired and nosocomial diseases. Many of the illnesses caused by these bacteria could be treated with beta-lactams for several decades. The increasing use of carbapenems for the treatment of diseases caused by Enterobacteriaceae expressing extended spectrum beta-lactamases, however, lead to the selection and spread of carbapenemase-producing pathogens. Such bacteria are not only resistant to virtually all beta-lactams, but also to numerous other antibiotics such as quinolones, co-trimoxazole, nitrofurantoin, tetracyclines and most aminoglycosides. During the last years, carbapenemase-producing Enterobacteriaceae have spread into almost all regions of the world. Klebsiella pneumoniae carbapenemases (KPC, belonging to Ambler class A), OXA-48 enzymes and their derivatives (belonging to Ambler class D) as well as some metallo-beta-lactamases (Ambler class B) such as NDM, VIM and IMP are the most important carbapenemases produced by Enterobacteriaceae strains. In Germany, the metallo-carbapenemase GIM-1, which has never been proven in bacteria outside Germany, is also of clinical significance. There is no established antibacterial therapy for these difficult-to-treat diseases. For the treatment of severe diseases caused by carbapenemase-producing bacteria, fosfomycin, gentamicin and tigecycline, polymyxins such as polymyxin B or colistin as well as carbapenems, are frequently applied. Combination antibiotic treatment may be more effective than monotherapy for severe ill patients with serious diseases. The most promising new treatment options arise with the development of avibactam. This non-beta-lactam beta-lactamase inhibitor shows good activity against (nearly) all class A and class C beta-lactamases (including strains expressing class A carbapenemases and/or derepressed AmpC enzymes) as well as OXA-48 carbapenemases. It may be used successfully in combination with ceftazidime, ceftaroline or aztreonam. PMID:24908928
Stock, Ingo
Injectable bioadhesive hydrogels with innate antibacterial properties
NASA Astrophysics Data System (ADS)
Surgical site infections cause significant postoperative morbidity and increased healthcare costs. Bioadhesives used to fill surgical voids and support wound healing are typically devoid of antibacterial activity. Here we report novel syringe-injectable bioadhesive hydrogels with inherent antibacterial properties prepared from mixing polydextran aldehyde and branched polyethylenimine. These adhesives kill both Gram-negative and Gram-positive bacteria, while sparing human erythrocytes. An optimal composition of 2.5?wt% oxidized dextran and 6.9?wt% polyethylenimine sets within seconds forming a mechanically rigid (~\
Giano, Michael C.; Ibrahim, Zuhaib; Medina, Scott H.; Sarhane, Karim A.; Christensen, Joani M.; Yamada, Yuji; Brandacher, Gerald; Schneider, Joel P.
Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification
One of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated Ki ranging from 4 to 250 ?M (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification. PMID:22933186
Ballester, Pedro J.; Mangold, Martina; Howard, Nigel I.; Robinson, Richard L. Marchese; Abell, Chris; Blumberger, Jochen; Mitchell, John B. O.
Preparation and Antibacterial Activity Evaluation of 18-?-glycyrrhetinic Acid Loaded PLGA Nanoparticles
The aim of the present study was to formulate poly (lactide-co-glycolide) (PLGA) nanoparticles loaded with 18-?-glycyrrhetinic acid (GLA) with appropriate physicochemical properties and antimicrobial activity. GLA loaded PLGA nanoparticles were prepared with different drug to polymer ratios, acetone contents and sonication times and the antibacterial activity of the developed nanoparticles was examined against different gram-negative and gram-positive bacteria. The antibacterial effect was studied using serial dilution technique to determine the minimum inhibitory concentration of nanoparticles. Results demonstrated that physicochemical properties of nanoparticles were affected by the above mentioned parameters where nanoscale size particles ranging from 175 to 212Ānm were achieved. The highest encapsulation efficiency (53.2Ā▒Ā2.4%) was obtained when the ratio of drug to polymer was 1:4. Zeta potential of the developed nanoparticles was fairly negative (-11▒1.5). In-vitro release profile of nanoparticles showed two phases: an initial phase of burst release for 10 h followed by a slow release pattern up to the end. The antimicrobial results revealed that the nanoparticles were more effective than pure GLA against P. aeuroginosa, S. aureus and S. epidermidis.ĀThis improvement in antibacterial activity of GLA loaded nanoparticles when compared to pure GLA may be related to higher nanoparticles penetration into infected cells and a higher amount of GLA delivery in its site of action. Herein, it was shown that GLA loaded PLGA nanoparticles displayed appropriate physicochemical properties as well as an improved antimicrobial effect.
Darvishi, Behrad; Manoochehri, Saeed; Kamalinia, Golnaz; Samadi, Nasrin; Amini, Mohsen; Mostafavi, Seyyed Hossein; Maghazei, Shahab; Atyabi, Fatemeh; Dinarvand, Rassoul
Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or ōImmuno-Fairy Talesö?
Professional phagocytes (polymorphonuclear neutrophils and monocytes/macrophages) are a main component of the immune system. These cells are involved in both host defenses and various pathological settings characterized by excessive inflammation. Accordingly, they are key targets for immunomodulatory drugs, among which antibacterial agents are promising candidates. The basic and historical concepts of immunomodulation will first be briefly reviewed. Phagocyte complexity will then be unravelled (at least in terms of what we know about the origin, subsets, ambivalent roles, functional capacities, and transductional pathways of this cell and how to explore them). The core subject of this review will be the many possible interactions between antibacterial agents and phagocytes, classified according to demonstrated or potential clinical relevance (e.g., neutropenia, intracellular accumulation, and modulation of bacterial virulence). A detailed review of direct in vitro effects will be provided for the various antibacterial drug families, followed by a discussion of the clinical relevance of these effects in two particular settings: immune deficiency and inflammatory diseases. The prophylactic and therapeutic use of immunomodulatory antibiotics will be considered before conclusions are drawn about the emerging (optimistic) vision of future therapeutic prospects to deal with largely unknown new diseases and new pathogens by using new agents, new techniques, and a better understanding of the phagocyte in particular and the immune system in general. PMID:11023961
Labro, Marie-Thķrķse
Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity
The cyclic acyldepsipeptide (ADEP) antibiotics are a new class of antibacterial agents that kill bacteria via a mechanism that is distinct from all clinically used drugs. These molecules bind and dysregulate the activity of the ClpP peptidase. The potential of these antibiotics as antibacterial drugs has been enhanced by the elimination of pharmacological liabilities through medicinal chemistry efforts. Here, we demonstrate that the ADEP conformation observed in the ADEP¢ClpP crystal structure is fortified by transannular hydrogen bonding and can be further stabilized by judicious replacement of constituent amino acids within the peptidolactone core structure with more conformationally constrained counterparts. Evidence supporting constraint of the molecule into the bioactive conformer was obtained by measurements of deuterium-exchange kinetics of hydrogens that were proposed to be engaged in transannular hydrogen bonds. We show that the rigidified ADEP analogs bind and activate ClpP at lower concentrations in vitro. Remarkably, these compounds have up to 1200-fold enhanced antibacterial activity when compared to those with the peptidolactone core structure common to two ADEP natural products. This study compellingly demonstrates how rational modulation of conformational dynamics may be used to improve the bioactivities of natural products. PMID:24422534
Natural products as antibacterial agents
For thousands of years medicinal plants have played a significant role in the treatment of a wide range of medical conditions, including infectious diseases. Some naturally occurring chemical compounds serve as models for a large percentage clinically proven drugs, and many are now being re-assessed as antimicrobial agents. The primary reason for this renaissance is the fact that infectious disease
Gail B. Mahady; Yue Huang; Brian J. Doyle; Tracie Locklear
Study on antibacterial mechanism of copper-bearing austenitic antibacterial stainless steel by atomic force microscopy.
A study was made on the antibacterial mechanism of copper-bearing austenitic antibacterial stainless steel by a series of methods such as atomic force microscopy (AFM) observation, force-distance curves and inductively coupled plasma mass spectrometer test. It was observed by AFM that the structure of the outer cell membrane responsible for the cell permeability was substantially changed for the bacteria after contacting with the antibacterial stainless steel, showing that cell walls were seriously damaged and a lot of contents in the cells leaked. It was also found that the adhesion force of bacteria to antibacterial stainless steel was considerably greater than that to the contrast steel, indicating that the electrostatic forces by Cu(2+ )being an important factor for killing bacteria. PMID:18392666
Nan, Li; Liu, Yongqian; L³, Manqi; Yang, Ke
QapR (PA5506) Represses an Operon That Negatively Affects the Pseudomonas Quinolone Signal in Pseudomonas aeruginosa
Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen that can cause disease in varied sites within the human body and is a significant source of morbidity and mortality in those afflicted with cystic fibrosis. P. aeruginosa is able to coordinate group behaviors, such as virulence factor production, through the process of cell-to-cell signaling. There are three intercellular signaling systems employed by P. aeruginosa, and one of these systems utilizes the small molecule 2-heptyl-3-hydroxy-4-quinolone (Pseudomonas quinolone signal [PQS]). PQS is required for virulence in multiple infection models and has been found in the lungs of cystic fibrosis patients colonized by P. aeruginosa. In this study, we have identified an RpiR family transcriptional regulator, QapR, which is an autoregulatory repressor. We found that mutation of qapR caused overexpression of the qapR operon. We characterized the qapR operon to show that it contains genes qapR, PA5507, PA5508, and PA5509 and that QapR directly controls the transcription of these genes in a negative manner. We also show that derepression of this operon greatly reduces PQS concentration in P. aeruginosa. Our results suggest that qapR affects PQS concentration by repressing an enzymatic pathway that acts on PQS or a PQS precursor to lower the PQS concentration. We believe that this operon comprises a novel mechanism to regulate PQS concentration in P. aeruginosa. PMID:23708133
Tipton, Kyle A.; Coleman, James P.
Pseudomonas aeruginosa Alkyl Quinolones Repress Hypoxia-Inducible Factor 1 (HIF-1) Signaling through HIF-1? Degradation
The transcription factor hypoxia-inducible factor 1 (HIF-1) has recently emerged to be a crucial regulator of the immune response following pathogen perception, including the response to the important human pathogen Pseudomonas aeruginosa. However, as mechanisms involved in HIF-1 activation by bacterial pathogens are not fully characterized, understanding how bacteria and bacterial compounds impact on HIF-1? stabilization remains a major challenge. In this context, we have focused on the effect of secreted factors of P. aeruginosa on HIF-1 regulation. Surprisingly, we found that P. aeruginosa cell-free supernatant significantly repressed HIF-1? protein levels. Further characterization revealed that HIF-1? downregulation was dependent on a subset of key secreted factors involved in P. aeruginosa pathogenesis, the 2-alkyl-4-quinolone (AQ) quorum sensing (QS) signaling molecules, and in particular the pseudomonas quinolone signal (PQS). Under hypoxic conditions, the AQ-dependent downregulation of HIF-1? was linked to the suppressed induction of the important HIF-1 target gene hexokinase II. Furthermore, we demonstrated that AQ molecules directly target HIF-1? protein degradation through the 26S-proteasome proteolytic pathway but independently of the prolyl hydroxylase domain (PHD). In conclusion, this is the first report showing that bacterial molecules can repress HIF-1? protein levels. Manipulation of HIF-1 signaling by P. aeruginosa AQs could have major consequences for the host response to infection and may facilitate the infective properties of this pathogen. PMID:22949552
Legendre, Claire; Reen, F. Jerry; Mooij, Marlies J.; McGlacken, Gerard P.; Adams, Claire
Pseudomonas aeruginosa Alkyl quinolones repress hypoxia-inducible factor 1 (HIF-1) signaling through HIF-1? degradation.
The transcription factor hypoxia-inducible factor 1 (HIF-1) has recently emerged to be a crucial regulator of the immune response following pathogen perception, including the response to the important human pathogen Pseudomonas aeruginosa. However, as mechanisms involved in HIF-1 activation by bacterial pathogens are not fully characterized, understanding how bacteria and bacterial compounds impact on HIF-1? stabilization remains a major challenge. In this context, we have focused on the effect of secreted factors of P. aeruginosa on HIF-1 regulation. Surprisingly, we found that P. aeruginosa cell-free supernatant significantly repressed HIF-1? protein levels. Further characterization revealed that HIF-1? downregulation was dependent on a subset of key secreted factors involved in P. aeruginosa pathogenesis, the 2-alkyl-4-quinolone (AQ) quorum sensing (QS) signaling molecules, and in particular the pseudomonas quinolone signal (PQS). Under hypoxic conditions, the AQ-dependent downregulation of HIF-1? was linked to the suppressed induction of the important HIF-1 target gene hexokinase II. Furthermore, we demonstrated that AQ molecules directly target HIF-1? protein degradation through the 26S-proteasome proteolytic pathway but independently of the prolyl hydroxylase domain (PHD). In conclusion, this is the first report showing that bacterial molecules can repress HIF-1? protein levels. Manipulation of HIF-1 signaling by P. aeruginosa AQs could have major consequences for the host response to infection and may facilitate the infective properties of this pathogen. PMID:22949552
Legendre, Claire; Reen, F Jerry; Mooij, Marlies J; McGlacken, Gerard P; Adams, Claire; O'Gara, Fergal
Thieno[2,3-d]pyrimidinedione derivatives as antibacterial agents
Several thieno[2,3-d]pyrimidinediones have been synthesized and examined for antibacterial activity against a range of Gram-positive and Gram-negative pathogens. Two compounds displayed potent activity (2¢16 mg/L) against multi-drug resistant Gram-positive organisms, including methicillin, vancomycin-intermediate, and vancomycin-resistant Staphylococcus aureus (MRSA, VISA, VRSA) and vancomycin-resistant enterococci (VRE). Only one of these agents possessed moderate activity (16¢32 mg/L) against Gram-negative strains. An examination of the cytotoxicity of these agents revealed that they displayed low toxicity (40¢50 mg/L) against mammalian cell and very low hemolytic activity (2¢7%). Taken together, these studies suggest that thieno[2,3-d]pyrimidinediones are interesting scaffolds for the development of novel Gram-positive antibacterial agents. PMID:22405289
Dewal, Mahender B.; Wani, Amit S.; Vidaillac, Celine; Oupicky, David; Rybak, Michael J.
Sesbania grandiflora leaf extract mediated green synthesis of antibacterial silver nanoparticles against selected human pathogens
NASA Astrophysics Data System (ADS)
Simple, effective and rapid approach for the green synthesis of silver nanoparticles (AgNPs) using leaf extract of Sesbania grandiflora and their in vitro antibacterial activity against selected human pathogens has been demonstrated in the study. Various instrumental techniques were adopted to characterize the synthesized AgNPs viz. UV-Vis, FTIR, XRD, TEM, EDX and AFM. Surface Plasmon spectra for AgNPs are centered at 422 nm with dark brown color. The synthesized AgNPs were found to be spherical in shape with size in the range of 10-25 nm. The presence of water soluble proteins in the leaf extract was identified by FTIR which were found to be responsible for the reduction of silver ions (Ag+) to AgNPs. Moreover, the synthesized AgNPs showed potent antibacterial activity against multi-drug resistant (MDR) bacteria such as Salmonella enterica and Staphylococcus aureus.
Das, J.; Paul Das, M.; Velusamy, P.
Synthesis of mimics of pramanicin from pyroglutamic Acid and their antibacterial activity.
Epoxypyrrolidinones are available by epoxidation of carboxamide-activated bicyclic lactam substrates derived from pyroglutamate using aqueous hydrogen peroxide and tertiary amine catalysis. In the case of an activating Weinreb carboxamide, further chemoselective elaboration leads to the efficient formation of libraries of epoxyketones. Deprotection may be achieved under acidic conditions to give epoxypyroglutaminols, although the ease of this process can be ameliorated by the presence of internal hydrogen bonding. Bioassay against S. aureus and E. coli indicated that some compounds exhibit antibacterial activity. These libraries may be considered to be structural mimics of the natural products pramanicin and epolactaene. More generally, this outcome suggests that interrogation of bioactive natural products is likely to permit the identification of "privileged" structural scaffolds, providing frameworks suitable for optimization in a short series of chemical steps that may accelerate the discovery of new antibiotic chemotypes. Further optimization of such systems may permit the rapid identification of novel systems suitable for antibacterial drug development. PMID:25647715
Tan, Song Wei Benjamin; Chai, Christina L L; Moloney, Mark G; Thompson, Amber L
Synthesis and antibacterial activity of naphthyridone derivatives containing mono/difluoro-methyloxime pyrrolidine scaffolds.
A series of novel naphthyridone derivatives containing mono/difluoro-methyloxime pyrrolidine scaffolds were designed and synthesized. These derivatives were initially evaluated for their inĀvitro antibacterial activity and compounds 13a1, b1 were chosen for further evaluation their inĀvivo activity against systemic infections in mice. The results indicate that all of the target compounds have considerable inĀvitro antibacterial activity. In the inĀvivo experiments, 13b1 was found to be more effective than the parent drug gemifloxacin against the tested five strains, and especially its activity (ED(50):21.27Āmg/kg) is 5.2-6.1 times more potent than gemifloxacin and ciprofloxacin against clinically important Gram-negative pathogen Pseudomonas aeruginosa. PMID:22079379
Lv, Kai; Liu, Ming-Liang; Feng, Lian-Shun; Sun, Lan-Ying; Sun, Ye-Xin; Wei, Zeng-Quan; Guo, Hui-Quan
In Vitro Activity of Five Quinolones and Analysis of the Quinolone Resistance-Determining Regions of gyrA, gyrB, parC, and parE in Ureaplasma parvum and Ureaplasma urealyticum Clinical Isolates from Perinatal Patients in Japan.
Ureaplasma spp. cause several disorders, such as nongonococcal urethritis, miscarriage, and preterm delivery with lung infections in neonates, characterized by pathological chorioamnionitis in the placenta. Although reports on antibiotic resistance in Ureaplasma are on the rise, reports on quinolone-resistant Ureaplasma infections in Japan are limited. The purpose of this study was to determine susceptibilities to five quinolones of Ureaplasma urealyticum and Ureaplasma parvum isolated from perinatal samples in Japan and to characterize the quinolone resistance-determining regions in the gyrA, gyrB, parC, and parE genes. Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L. Among 158 samples, the ParC S83L mutation was found in 37 samples (23.4%), including 1 sample harboring a ParC S83L-GyrB P462S double mutant. Novel mutations of ureaplasmal ParC (S83W and S84P) were independently found in one of the samples. Homology modeling of the ParC S83W mutant suggested steric hindrance of the quinolone-binding pocket (QBP), and de novo prediction of peptide structures revealed that the ParC S84P may break/kink the formation of the ?4 helix in the QBP. Further investigations are required to unravel the extent and mechanism of antibiotic resistance of Ureaplasma spp. in Japan. PMID:25645833
Kawai, Yasuhiro; Nakura, Yukiko; Wakimoto, Tetsu; Nomiyama, Makoto; Tokuda, Tsugumichi; Takayanagi, Toshimitsu; Shiraishi, Jun; Wasada, Kenshi; Kitajima, Hiroyuki; Fujita, Tomio; Nakayama, Masahiro; Mitsuda, Nobuaki; Nakanishi, Isao; Takeuchi, Makoto; Yanagihara, Itaru
Antibacterial and antioxidant activities of Musa sp. leaf extracts against multidrug resistant clinical pathogens causing nosocomial infection
Objective To investigate different Musa sp. leave extracts of hexane, ethyl acetate and methanol were evaluated for antibacterial activity against multi-drug resistant pathogens causing nosocomial infection by agar well diffusion method and also antioxidant activities. Methods The four different Musa species leaves were extracted with hexane, ethyl acetate and methanol. Antibacterial susceptibility test, minimum inhibitory concentration and minimum inhibitory bacterial concentration were determined by agar well diffusion method. Total phenolic content and in vitro antioxidant activity was determined. Results All the Musa sp. extracts showed moderate antibacterial activities expect Musa paradisiaca with the inhibition zone ranging from 8.0 to 18.6 mm. Among four species ethyl acetate extracts of Musa paradisiaca showed highest activity against tested pathogens particularly E. coli, P. aeruginosa and Citrobacter sp. The minimum inhibitory concentrations were within the value of 15.63- 250 Ąg/mL and minimum bactericidal concentrations were ranging from 31.25- 250 Ąg/mL. Antioxidant activity of Musa acuminate exhibited maximum activity among other three Musa species. Conclusions The present study concluded that among the different Musa species, Musa paradisiaca displayed efficient antibacterial activity followed by Musa acuminata against multi-drug resistant nosocomial infection causing pathogens. Further, an extensive study is needed to identify the bioactive compounds, mode of action and toxic effect in vivo of Musa sp. PMID:23998016
Karuppiah, Ponmurugan; Mustaffa, Muhammed
Outer membrane proteins responsible for multiple drug resistance in Pseudomonas aeruginosa.
Three types of multiple-drug-resistant mutants which were phenotypically similar to previously described nalB, nfxB, and nfxC mutants were isolated from Pseudomonas aeruginosa PAO1 and two clinical isolates. Type 1 (nalB-type) mutants showed cross-resistance to meropenem, cephems, and quinolones. They overproduced an outer membrane protein with an apparent molecular mass of 50 kDa (OprM). Type 2 (nfxB-type) mutants showed cross-resistance to quinolones and new cephems, i.e., cefpirome and cefozopran, concomitant with overproduction of an outer membrane protein with an apparent molecular mass of 54 kDa (OprJ). Type 3 (nfxC-type) mutants showed cross-resistance to carbapenems and quinolones. They produced decreased amounts of OprD and increased amounts of a 50-kDa protein (OprN), which was almost the same molecular weight as that of OprM, but it was distinguishable from OprM by its heat modifiability on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In the presence of salicylate, the parent strains showed an increased level of resistance to carbapenems and quinolones and produced decreased amounts of OprD and increased amounts of OprN. Salicylate caused the repression of OprJ production and the loss of resistance to cefpirome and cefozopran in two of the three OprJ-overproducing mutants, although salicylate slightly increased the level of resistance in the parent strains. The changes in susceptibilities were transient in the presence of salicylate. These data suggest that at least three different outer membrane proteins, OprM, OprJ, and OprN, are associated with multiple drug resistance in P. aeruginosa. PMID:7793866
Masuda, N; Sakagawa, E; Ohya, S
Zulu medicinal plants with antibacterial activity
Aqueous, methanolic and ethyl acetate extracts of 14 plants used in traditional Zulu medicine for treatment of ailments of an infectious nature were screened for antibacterial activity. Most of the activity detected was against Gram-positive bacteria. Tuber bark extracts of Dioscorea sylvatica had activity against Gram-negative Escherichia coli and extracts of Dioscorea dregeana, Cheilanthes viridis and Vernonia colorata were active
Jonathan E. Kelmanson; Anna K. Jõger; Johannes van Staden
Antibacterial Activity of Retinaldehyde against Propionibacterium acnes
Background: Retinaldehyde has been shown to exert antibacterial activity in vitro. Aim: This study evaluates the effect of retinaldehyde on Propionibacterium acnes both in vivo and in vitro. Methods: Microbial minimal inhibitory concentrations (MICs) of retinaldehyde and retinoic acid were determined on reference strains of P. acnes. In vivo activity of daily topical application of 0.05% retinaldehyde on the P.
M. PechĶre; J.-C. PechĶreb; L. Germaniera
Long-Circulating Bacteriophage as Antibacterial Agents
The increased prevalence of multidrugresistant bacterial pathogens motivated us to attempt to enhance the therapeutic efficacy of bacteriophages. The therapeutic application of phages as antibacterial agents was impeded by several factors: (i) the failure to recognize the relatively narrow host range of phages; (ii) the presence of toxins in crude phage lysates; and (iii) a lack of appreciation for the
Carl R. Merril; Biswajit Biswas; Richard Carlton; Nicole C. Jensen; G. Joseph Creed; Steve Zullo; Sankar Adhya
Two attacin antibacterial genes of Drosophila melanogaster
Insects express a battery of potent antimicrobial proteins in response to injury and infection. Recent work from several laboratories has demonstrated that this response is neither stereotypic nor completely nonspecific, and that different pathways are responsible for inducing the expression of antifungal and antibacterial peptides. Here we report the cloning of two closely linked attacin genes from Drosophila melanogaster. We
Mitchell S. Dushay; Joseph B. Roethele; Josķ M. Chaverri; Daniel E. Dulek; Samreen K. Syed; Toshimori Kitami; Elizabeth D. Eldon
Antibacterial Activity of Honey on Cariogenic Bacteria
Objective: Honey has antibacterial activity. The aim of this study was to evaluate the antibacterial activity of honey on Streptococcus mutans and Lactobacillus. Materials and Methods: In this in vitro study, solutions containing 0%, 5%, 10%, 20%, 50% and 100%(w/v) of natural Hamadan honey were prepared. Each blood (nutrient) agar plate was then filled with dilutions of the honey. The strains of bacteria were inoculated in blood agar for 24 hours at 37░C and were adjusted according to the McFarland scale (10ū10 cfumcl?1). All assays were repeated 10 times for each of the honey concentrations. Data were analyzed by non parametric Chi-Square test. Statistical significance was set at ?=0.05. Results: Significant antibacterial activity was detected for honey on Streptococcus mutans in concentrations more than 20% and on Lactobacillus in 100% concentration (P<0.05). Conclusion: It seems that antibacterial activity of honey could be used for prevention and reduction of dental caries. PMID:23724198
Ahmadi ¢ Motamayel, Fatemeh; Hendi, Seyedeh Sare; Alikhani, Mohammad Yusof; Khamverdi, Zahra
Chemical biology Antibacterial sugar-tipped
Chemical biology Antibacterial sugar-tipped trees J. Am. Chem. Soc. 126, 4750┬Ł4751 (2004) Enzymes proteins in the bacterial cell walls, which bind to sugar (galactose) molecules. Rendle et al. figured on the proteases. Dendrons with two, three or four sugar tips give the enzyme a secure hold, with two tips being
Davis, Ben G.
Antibacterial activity of some medicinal plant extracts
Antibacterial activity of hot aqueous and methanolic extracts prepared from six plants (Terminallia chebula, Terminallia bellerica, Phyllanthus emblica, Punica granatum, Lawsonia alba and Mikania micrantha) used in traditional folk medicines of India were screened against five pathogenic bacteria (Staphylococcus aureus MTCC 2940, Bacillus subtilis MTCC 441, Escherichia coli MTCC 739, Proteus vulgaris MTCC 426 and Enterobacter aerogenes MTCC 111). The
Anupam Ghosh; Bidus Kanti Das; Arup Roy; Biplab Mandal; Goutam Chandra
Development of a copper-catalyzed amidation-base-promoted cyclization sequence for the synthesis of 2-aryl- and 2-vinyl1-4 quinolones
A direct two-step method for the preparation of 2-aryl- and 2-vinyl-4-quinolones that utilizes a copper-catalyzed amidation of ortho-halophenones followed by a base-promoted Camps cyclization of the resulting N-(2-keto-aryl)amides ...
Jones, Carrie Preston
Trace enrichment of (fluoro)quinolone antibiotics in surface waters by solid-phase extraction and their determination by liquid chromatography-ultraviolet detection.
A new and simple analytical methodology for the simultaneous analysis of acidic and zwitterionic (fluoro)quinolones in surface waters at trace concentration level is presented. The method is based on the preconcentration of these analytes by a solid-phase extraction procedure and their subsequent quantification by liquid chromatography using ultraviolet detection. The breakthrough volumes of the selected (fluoro)quinolones in four different sorbents--C18, styrenedivinylbenzene (SDB), C18-cation-exchange and SDB-cation-exchange--have been evaluated and varied between 25 and 150 ml depending on the antibiotic and the sorbent used. An exhaustive study of the influence of sample pH on the preconcentration step has been carried out in order to find a suitable procedure for extraction of acidic and zwitterionic FQs in one single step. Under optimum conditions, it was possible to percolate up to 250 ml of water solution onto both C18 and SDB-cation-exchange cartridges with quantitative recoveries for all the analytes tested. However, matrix components of the surface water samples analysed negatively affected the recoveries of the analytes in the SDB-cation-exchange cartridge and thus, C18 cartridges were finally selected for the analysis of the (fluoro)quinolones in lake and river water. The limits of detection achieved with this procedure varied between 8 and 20 ng l(-1) proving its suitability for the determination of the (fluoro)quinolones in water samples at a realistic environmental concentration level. PMID:12967179
Turiel, Esther; Bordin, Guy; RodrĒguez, Adela R
L,L-diaminopimelate aminotransferase (DapL): a putative target for the development of narrow-spectrum antibacterial compounds
Despite the urgent need for sustained development of novel antibacterial compounds to combat the drastic rise in antibiotic resistant and emerging bacterial infections, only a few clinically relevant antibacterial drugs have been recently developed. One of the bottlenecks impeding the development of novel antibacterial compounds is the identification of new enzymatic targets. The nutritionally essential amino acid anabolic pathways, for example lysine biosynthesis, provide an opportunity to explore the development of antibacterial compounds, since human genomes do not possess the genes necessary to synthesize these amino acids de novo. The diaminopimelate (DAP)/lysine (lys) anabolic pathways are attractive targets for antibacterial development since the penultimate lys precursor meso-DAP (m-DAP) is a cross-linking amino acid in the peptidoglycan (PG) cell wall of most Gram-negative bacteria and lys plays a similar role in the PG of most Gram-positive bacteria, in addition to its role as one of the 20 proteogenic amino acids. The L,L-diaminopimelate aminotransferase (DapL) pathway was recently identified as a novel variant of the DAP/lys anabolic pathways. The DapL pathway has been identified in the pathogenic bacteria belonging to the genus; Chlamydia, Leptospira, and Treponema. The dapL gene has been identified in the genomes of 381 or approximately 13% of the 2771 bacteria that have been sequenced, annotated and reposited in the NCBI database, as of May 23, 2014. The narrow distribution of the DapL pathway in the bacterial domain provides an opportunity for the development and or discovery of narrow spectrum antibacterial compounds. PMID:25309529
Triassi, Alexander J.; Wheatley, Matthew S.; Savka, Michael A.; Gan, Han Ming; Dobson, Renwick C. J.; Hudson, Andrķ O.
Simultaneous determination of multiple (fluoro)quinolone antibiotics in food samples by a one-step fluorescence polarization immunoassay.
This paper describes a rapid one-step fluorescence polarization immunoassay (FPIA) for the simultaneous determination of multiple (fluoro)quinolone antibiotics (FQs) in food samples. Several fluorescent tracers were synthesized and evaluated in the FPIA method based on a broad-specificity of monoclonal antibodies toward FQs. The heterogeneous tracer, SAR-5-FAM, was considered as the optimal choice to prepare the immunocomplex single reagent, which allows a rapid and sensitive displacement reaction by addition of analytes. Optimized single-reagent FPIA exhibited broad cross-reactivities in the range of 7.8-172.2% with 16 FQs tested and was capable of determining most FQs at the level of maximum residue limits. Recoveries for spiked milk and chicken muscle samples were from 77.8 to 116%, with relative standard deviation lower than 17.4%. Therefore, this method could be applicable in routine screening analysis of multiple FQ residues in food samples. PMID:24050679
Mi, Tiejun; Wang, Zhanhui; Eremin, Sergei A; Shen, Jianzhong; Zhang, Suxia
Over-expression of bael quinolone synthase in tobacco improves plant vigor under favorable conditions, drought, or salt stress.
Type III polyketide synthases (PKSs) catalyze the biosynthesis of various medicinally important secondary metabolites in plants, but their role in growth and stress response is unclear. Here, we overexpressed quinolone synthase (QNS) from bael in tobacco. QNS-overexpressing plants showed an overall increase in growth, photosynthetic efficiency and chlorophyll content compared to wild type plants. Second-generation (T2) transgenic plants grew to maturity, flowered early and set viable seeds under favorable conditions without yield penalty. An increased accumulation of flavonoids, phenols and alkaloids was associated with higher tolerance to drought and salinity stress in transgenic plants. Thus, bael QNS seems to function as a positive regulator of plant growth and stress response, and could be potentially used for engineering plants tolerant to abiotic stress. PMID:25555382
Resmi, Mohankumar Saraladevi; Vivek, Padmanabhan Jayanthi; Soniya, Eppurathu Vasudevan
Characterization of carbapenemases, extended spectrum ?-lactamases, quinolone resistance and aminoglycoside resistance determinants in carbapenem-non-susceptible Escherichia coli from a teaching hospital in Chongqing, Southwest China.
Carbapenem-resistant Escherichiacoli isolates harboring carbapenemases or combining an extended-spectrum ?-lactamase (ESBL) enzyme with loss of porins present an increasingly urgent clinical danger. Combined resistance to aminoglycosides and fluoroquinolones in carbapeneme non-susceptible (CNS) isolates will inevitably create problems. In the current study, we characterized the carbapenemases and ESBLs, and the prevalence of quinolone resistance determinants and aminoglycoside resistance determinants in carbapenem-non-susceptible (CNS) E.coli isolates from a teaching hospital in Chongqing, Southwest China in 2012. Thirty non-duplicated CNS E.coli isolates were screened via antimicrobial susceptibility testing, and the drug resistance profiles of the 30 strains were analyzed. Carbapenemase genes blaKPC-2, ESBL genes including blaCTX-M-3, blaCTX-M-14, blaCTX-M-55 and blaTEM, ARD genes including aac(6')-Ib, armA and rmtB, and QRD genes including qnrA, qnrB, qnrC, qnrD, qnrS and aac(6')-Ib-cr were identified and clonal relatedness was investigated by pulsed-field gel electrophoresis. Of the 30 isolates, 2 (6.7%) harbored carbapenemase gene blaKPC-2; 29 (96.7%) carried ESBLs; 20 (66.7%) were QRD positive; and 11 (36.7%) were ARD positive. Between the two blaKPC-2 positive strains, one contained ESBL, QRD and ARD genes, while the other expressed ESBL genes but was negative for both QRD and ARD genes. Of the 29 ESBLs positive isolates, 2 (6.9%) were carbapenemase positive, 19 (65.5%) were QRD positive, and 11 (37.9%) were ARD positive. PFGE revealed genetic diversity among the 30 isolates, indicating that the high prevalence of CNS E. coli isolates was not caused by clonal dissemination. Production of ESBLs was associated with the carbapenem resistance and QRD genes were highly prevalent among the CNS E. coli isolates. Multiple resistant genes were co-expressed in the same isolates. This is the first report of a multidrug resistant carbapenem-non-susceptible E.coli co-harboring resistant determinants blaKPC-2, blaCTX-M-14, blaCTX-M-55, blaTEM, aac(6')-Ib-cr, qnrB, aac(6')-Ib and rmtB from Chongqing, mainland China. PMID:25107431
Zhang, Chuanming; Xu, Xiuyu; Pu, Shuli; Huang, Shifeng; Sun, Jide; Yang, Shuangshuang; Zhang, Liping
Enhanced antibacterial activity in Hydra polyps lacking nerve cells.
The nervous system evolved within cnidarians. When assessing antibacterial activity in the freshwater polyp Hydra, we observed a strong correlation between the number of neurons present and the antibacterial activity. Tissue lacking neurons had a drastically enhanced antibacterial activity against Gram-positive (Bacillus subtilis) and Gram-negative (E. coli) bacteria compared to control tissue. The results indicate direct and strong neural influences on immunity in the phylogenetically oldest animals having a nervous system. PMID:12543122
Kasahara, Shinji; Bosch, Thomas C G
Alternative strategies for proof-of-principle studies of antibacterial agents.
The proof that a new antibacterial agent is not only active in vitro but also effective in vivo under clinically relevant conditions is currently provided (i) by using appropriate nonclinical models of infection and pharmacokinetic-pharmacodynamic (PK-PD) analysis providing evidence of the likelihood of clinical efficacy and (ii) by examining the study drug in exploratory clinical trials, as well as dose and schedule finding during phase II of clinical development. This approach is both time-consuming and costly. Furthermore, PK-PD targets for any novel antibacterial agent cannot be derived from studies with experimental animals. Therefore, alternative strategies have to be identified to prove the principle that a novel antibacterial agent is active under clinically relevant conditions. This review summarizes evidence that the quantitative analysis of shifts in the viable counts of pathogens in infected patients or the evaluation of the PD effect of an investigational agent on indicator organisms of the human resident microflora or colonizers of healthy volunteers, if paralleled with PK monitoring of serum and the target site, provides an alternative to a classical proof-of-principle study in the course of a phase II study program. PMID:24867989
Dalhoff, Axel; Weintraub, Andrej; Nord, Carl Erik
Alternative Strategies for Proof-of-Principle Studies of Antibacterial Agents
The proof that a new antibacterial agent is not only active in vitro but also effective in vivo under clinically relevant conditions is currently provided (i) by using appropriate nonclinical models of infection and pharmacokinetic-pharmacodynamic (PK-PD) analysis providing evidence of the likelihood of clinical efficacy and (ii) by examining the study drug in exploratory clinical trials, as well as dose and schedule finding during phase II of clinical development. This approach is both time-consuming and costly. Furthermore, PK-PD targets for any novel antibacterial agent cannot be derived from studies with experimental animals. Therefore, alternative strategies have to be identified to prove the principle that a novel antibacterial agent is active under clinically relevant conditions. This review summarizes evidence that the quantitative analysis of shifts in the viable counts of pathogens in infected patients or the evaluation of the PD effect of an investigational agent on indicator organisms of the human resident microflora or colonizers of healthy volunteers, if paralleled with PK monitoring of serum and the target site, provides an alternative to a classical proof-of-principle study in the course of a phase II study program. PMID:24867989
Weintraub, Andrej; Nord, Carl Erik
Synthesis, Characterization, and Antibacterial Activity of Cross-Linked Chitosan-Glutaraldehyde
This present study deals with synthesis, characterization and antibacterial activity of cross-linked chitosan-glutaraldehyde. Results from this study indicated that cross-linked chitosan-glutaraldehyde markedly inhibited the growth of antibiotic-resistant Burkholderia cepacia complex regardless of bacterial species and incubation time while bacterial growth was unaffected by solid chitosan. Furthermore, high temperature treated cross-linked chitosan-glutaraldehyde showed strong antibacterial activity against the selected strain 0901 although the inhibitory effects varied with different temperatures. In addition, physical-chemical and structural characterization revealed that the cross-linking of chitosan with glutaraldehyde resulted in a rougher surface morphology, a characteristic Fourier transform infrared (FTIR) band at 1559 cm?1, a specific X-ray diffraction peak centered at 2? = 15░, a lower contents of carbon, hydrogen and nitrogen, and a higher stability of glucose units compared to chitosan based on scanning electron microscopic observation, FTIR spectra, X-ray diffraction pattern, as well as elemental and thermo gravimetric analysis. Overall, this study indicated that cross-linked chitosan-glutaraldehyde is promising to be developed as a new antibacterial drug. PMID:23670533
Li, Bin; Shan, Chang-Lin; Zhou, Qing; Fang, Yuan; Wang, Yang-Li; Xu, Fei; Han, Li-Rong; Ibrahim, Muhammad; Guo, Long-Biao; Xie, Guan-Lin; Sun, Guo-Chang
The use of FTIR microscopy for the evaluation of anti-bacterial agents activity.
FTIR spectroscopy has been used by chemists as a powerful tool to characterize inorganic and organic compounds. In this study we examined the potential of FTIR microspectroscopy for early evaluation of the efficiency of anti-bacterial therapy. For this purpose, the effect of caffeic acid phenethyl ester (CAPE) and ampicillin on the development of bacterial infection in cell culture was examined. CAPE is one of the most active components of propolis which is a natural honeybee product with a potent anti-bacterial activity. Our results show early (2h post-treatment), unique and significant spectral indicators for successful treatment with CAPE although some of these biomarkers showed different trends in Gram (-) compared with Gram (+) bacteria. For instance, the intensity of bands at 682 and 1316 cm(-1) decreases in all examined Gram (-) bacterial strains while significantly increases in all examined Gram (+) bacterial strains. On the other hand, both Gram (+) and Gram (-) bacteria treated with ampicillin did not show any spectral differences compared with the control untreated bacteria. It seems that FTIR spectroscopy can be used as an effective tool for an early evaluation of the efficiency of the anti-bacterial effect of CAPE and probably other used drugs. PMID:19394246
Huleihel, Mahmoud; Pavlov, Valentina; Erukhimovitch, Vitaly
Cytocompatibility and Antibacterial Properties of Capping Materials
The aim of this study was to evaluate and compare the antimicrobial activity and cytocompatibility of six different pulp-capping materials: Dycal (Dentsply), Calcicur (Voco), Calcimol LC (Voco), TheraCal LC (Bisco), MTA Angelus (Angelus), and Biodentine (Septodont). To evaluate antimicrobial activity, materials were challenged in vitro with Streptococcus mutans, Streptococcus salivarius, and Streptococcus sanguis in the agar disc diffusion test. Cytocompatibility of the assayed materials towards rat MDPC-23 cells was evaluated at different times by both MTT and apoptosis assays. Results significantly differed among the different materials tested. Both bacterial growth inhibition halos and cytocompatibility performances were significantly different among materials with different composition. MTA-based products showed lower cytotoxicity and valuable antibacterial activity, different from calcium hydroxide-based materials, which exhibited not only higher antibacterial activity but also higher cytotoxicity. PMID:24959601
Arciola, Carla Renata; Monaco, Annachiara; Lombardini, Marco
Antibacterial activity of traditional Australian medicinal plants
Fifty-six ethanolic extracts of various parts of 39 plants used in traditional Australian Aboriginal medicine were investigated for their antibacterial activities against four Gram-positive (Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus and Streptococcus pyogenes) and four Gram-negative (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Salmonella typhimurium) bacterial species. In a plate-hole diffusion assay, 12 extracts inhibited the growth of one or
Enzo A Palombo; Susan J Semple
DNA cloning and organization of the Staphylococcus aureus gyrA and gyrB genes: close homology among gyrase proteins and implications for 4-quinolone action and resistance.
Staphylococcus aureus gyrA and gyrB genes, which encode the DNA gyrase A and B proteins, have been isolated and found to map contiguously. DNA sequence analysis revealed close homology between the S. aureus gyrase subunits and their counterparts in Bacillus subtilis and Escherichia coli, including several conserved amino acid residues whose substitution in E. coli confers resistance to 4-quinolones. These results are discussed in regard to quinolone resistance mechanisms in S. aureus. Images PMID:2160946
Hopewell, R; Oram, M; Briesewitz, R; Fisher, L M
Non-antibacterial tetracycline formulations: clinical applications in dentistry and medicine.
In 1983, it was first reported that tetracyclines (TCs) can modulate the host response, including (but not limited to) inhibition of pathologic matrix metalloproteinase (MMP) activity, and by mechanisms unrelated to the antibacterial properties of these drugs. Soon thereafter, strategies were developed to generate non-antibacterial formulations (subantimicrobial-dose doxycycline; SDD) and compositions (chemically modified tetracyclines; CMTs) of TCs as host-modulating drugs to treat periodontal and other inflammatory diseases. This review focuses on the history and rationale for the development of: (a) SDD which led to two government-approved medications, one for periodontitis and the other for acne/rosacea and (b) CMTs, which led to the identification of the active site of the drugs responsible for MMP inhibition and to studies demonstrating evidence of efficacy of the most potent of these, CMT-3, as an anti-angiogenesis agent in patients with the cancer, Kaposi's sarcoma, and as a potential treatment for a fatal lung disease (acute respiratory distress syndrome; ARDS). In addition, this review discusses a number of clinical studies, some up to 2 years' duration, demonstrating evidence of safety and efficacy of SDD formulations in humans with oral inflammatory diseases (periodontitis, pemphigoid) as well as medical diseases, including rheumatoid arthritis, post-menopausal osteopenia, type II diabetes, cardiovascular diseases, and a rare and fatal lung disease, lymphangioleiomyomatosis. PMID:23071896
Gu, Ying; Walker, Clay; Ryan, Maria E; Payne, Jeffrey B; Golub, Lorne M
Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial.
Linezolid is the first antibacterial to be approved from the oxazolidinone class. The drug has substantial antimicrobial activity against Gram-positive organisms such as streptococci, staphylococci and enterococci, including species resistant to conventional antibacterial treatment. Linezolid is fully bioavailable following oral administration when compared with intravenous administration. Maximum plasma linezolid concentrations are usually achieved between 1 and 2 hours after oral administration. Food slightly decreases the rate, but not the extent, of absorption. The distribution of linezolid is approximately equivalent to total body water, and there is low protein binding (31%) to serum albumin. The elimination half-life of linezolid is 5-7 hours, and twice-daily administration of 400-600 mg provides steady-state concentrations in the therapeutic range. Linezolid is mainly cleared by non-renal clearance to two metabolites and renal clearance of the parent compound. Approximately 50% of an administered dose appears in the urine as the two major metabolites, and approximately 35% appears as parent drug. A small degree of nonlinearity has been observed, with a 30% decrease in clearance after a 5-fold increase in dose. The nonlinearity is not relevant over the therapeutic dosage range. Plasma linezolid concentrations in elderly patients, patients with mild to moderate hepatic impairment or mild to severe renal impairment are similar to those achieved in young or healthy volunteers. Higher concentrations are observed in women as compared with men, but the difference is not sufficient to warrant an adjustment in dosage. In patients with severe renal impairment requiring haemodialysis, the exposure to the two primary metabolites was 7 to 8-fold higher than in patients with normal renal function. Therefore, linezolid should be used with caution in patients with severe renal insufficiency. A higher clearance of linezolid was found in children as compared with adults, and therefore higher daily dosages per kg bodyweight are required in children. There is no pharmacokinetic interaction when linezolid is coadministered with aztreonam, gentamicin or warfarin. Linezolid is a mild, reversible, inhibitor of monoamine oxidases A and B. Coadministration of linezolid with the adrenergic agents pseudoephedrine and phenylpropanolamine resulted in increases in blood pressure relative to these agents alone or to placebo. The degree of the change in blood pressure was within that associated with normal daily activities. No interaction was observed when linezolid was coadministered with the serotonergic agent dextromethorphan. PMID:14531724
Stalker, Dennis J; Jungbluth, Gail L
Glucosamine sulfate--environmental antibacterial activity.
We have recently showed antibacterial activity against E. coli in vitro of a trademark Mega-Gluflex-containing glucosamine sulfate (GS) and chondroitin sulfate (CS). The purpose of this study was to examine the antibacterial activity of GS as a new trademark Arthryl (Manufacturer Rottapharm Ltd, Ireland; Distributor in Israel Rafa Laboratories Ltd) in vitro. We used cabbage and chicken broths and milk (every media of 20 ml) left opened for 1 week with and without Arthryl supplements 1,500 mg, the content of one package of the medication. A similar volume (20 ml) is ingested in taking the medication. Experiments with three repeatable results were taken for consideration. Arthryl inhibited environmental bacterial colonies' growth in every media but fungi growth was not impaired. Milk stayed liquid for the whole week with supplement of the Arthryl compared with sour milk transformation without Arthryl. Sample B showed inhibitory properties of the bacterial colonies on the fungi growth. The sample with Arthryl showed progressive growth of fungi without bacterial growth after 10 days of follow up compared with bacterial growth on media without Arthryl. Glucosamine sulfate as a new trademark Arthryl has environmental antibacterial properties but does not inhibit growth of fungal colonies. PMID:19495827
Rozin, Alexander P
Antibacterial activity of dentinal bonding agents.
The susceptibility of five bacterial species to seven dentinal bonding agents was examined in vitro. Agar diffusion tests using filterpaper disks containing 10 microL each of conditioner, primer, or resin were performed on blood agar and mitis salivarius bacitracin agar. Chlorhexidine (0.2%) was used as a positive control. After incubation, zones of inhibited bacterial growth were measured. Of all the compounds tested, Gluma cleanser and Gluma etchant showed the strongest growth inhibition for all bacterial strains. No antibacterial effect was noted for Prisma Universal Bond 2 and Superlux Universal Bond 2 systems. The primers of Gluma, Denthesive, and Scotchbond 2 displayed antibacterial activity that, in some cases, was comparable to that of 0.2% chlorhexidine. Zones of inhibition were seen for the resin materials of Scotchbond 2 and Tripton with Streptococcus mutans, Streptococcus sanguis and Actinomyces viscosus. No inhibition was seen after these resins were cured, whereas the antibacterial effect of XR-Bond on S sanguis and A viscosus was not affected by light curing. PMID:8210322
Emilson, C G; Bergenholtz, G
Substrate independent silver nanoparticle based antibacterial coatings.
Infections arising from bacterial adhesion and colonization on medical device surfaces are a significant healthcare problem. Silver based antibacterial coatings have attracted a great deal of attention as a potential solution. This paper reports on the development of a silver nanoparticles based antibacterial surface that can be applied to any type of material surface. The silver nanoparticles were surface engineered with a monolayer of 2-mercaptosuccinic acid, which facilitates the immobilization of the nanoparticles to the solid surface, and also reduces the rate of oxidation of the nanoparticles, extending the lifetime of the coatings. The coatings had excellent antibacterial efficacy against three clinically significant pathogenic bacteria i.e. Staphylococcus epidermidis, Staphylococcus aureus and Pseudomonas aeruginosa. Studies with primary human fibroblast cells showed that the coatings had no cytotoxicity inĀvitro. Innate immune studies in cultures of primary macrophages demonstrated that the coatings do not significantly alter the level of expression of pro-inflammatory cytokines or the adhesion and viability of these cells. Collectively, these coatings have an optimal combination of properties that make them attractive for deposition on medical device surfaces such as wound dressings, catheters and implants. PMID:24630091
Taheri, Shima; Cavallaro, Alex; Christo, Susan N; Smith, Louise E; Majewski, Peter; Barton, Mary; Hayball, John D; Vasilev, Krasimir
Honey: its medicinal property and antibacterial activity
Indeed, medicinal importance of honey has been documented in the world's oldest medical literatures, and since the ancient times, it has been known to possess antimicrobial property as well as wound-healing activity. The healing property of honey is due to the fact that it offers antibacterial activity, maintains a moist wound condition, and its high viscosity helps to provide a protective barrier to prevent infection. Its immunomodulatory property is relevant to wound repair too. The antimicrobial activity in most honeys is due to the enzymatic production of hydrogen peroxide. However, another kind of honey, called non-peroxide honey (viz., manuka honey), displays significant antibacterial effects even when the hydrogen peroxide activity is blocked. Its mechanism may be related to the low pH level of honey and its high sugar content (high osmolarity) that is enough to hinder the growth of microbes. The medical grade honeys have potent in vitro bactericidal activity against antibiotic-resistant bacteria causing several life-threatening infections to humans. But, there is a large variation in the antimicrobial activity of some natural honeys, which is due to spatial and temporal variation in sources of nectar. Thus, identification and characterization of the active principle(s) may provide valuable information on the quality and possible therapeutic potential of honeys (against several health disorders of humans), and hence we discussed the medicinal property of honeys with emphasis on their antibacterial activities. PMID:23569748
Mandal, Manisha Deb; Mandal, Shyamapada
What makes a natural clay antibacterial?
Natural clays have been used in ancient and modern medicine, but the mechanism(s) that make certain clays lethal against bacterial pathogens has not been identified. We have compared the depositional environments, mineralogies, and chemistries of clays that exhibit antibacterial effects on a broad spectrum of human pathogens including antibiotic resistant strains. Natural antibacterial clays contain nanoscale (<200 nm), illite-smectite and reduced iron phases. The role of clay minerals in the bactericidal process is to buffer the aqueous pH and oxidation state to conditions that promote Fe(2+) solubility. Chemical analyses of E. coli killed by aqueous leachates of an antibacterial clay show that intracellular concentrations of Fe and P are elevated relative to controls. Phosphorus uptake by the cells supports a regulatory role of polyphosphate or phospholipids in controlling Fe(2+). Fenton reaction products can degrade critical cell components, but we deduce that extracellular processes do not cause cell death. Rather, Fe(2+) overwhelms outer membrane regulatory proteins and is oxidized when it enters the cell, precipitating Fe(3+) and producing lethal hydroxyl radicals. PMID:21413758
Williams, Lynda B; Metge, David W; Eberl, Dennis D; Harvey, Ronald W; Turner, Amanda G; Prapaipong, Panjai; Poret-Peterson, Amisha T
Antibacterial activity of pepducins, allosterical modulators of formyl peptide receptor signaling.
Pepducins containing a fatty acid linked to an amino acid sequence derived from cytosolic parts of a G-protein-coupled receptor (GPCR) constitute a new group of lipopeptide tools in GPCR studies. Pepducins corresponding to the third intracellular loop of formyl peptide receptor 2 (FPR2) activate human neutrophils, and we show here that, in addition, these allosteric modulators of receptor activity also kill bacteria. The functional dualism of FPR2 pepducins could potentially be explored as a novel class of antibacterial drugs with immunomodulatory properties. PMID:24590483
Winther, Malene; Gabl, Michael; Oprea, Tudor I; J÷nsson, Bodil; Boulay, Francois; Bylund, Johan; Dahlgren, Claes; Forsman, Huamei
Fabrication of magnetite-based core-shell coated nanoparticles with antibacterial properties.
We report the fabrication of biofunctionalized magnetite core/sodium lauryl sulfate shell/antibiotic adsorption-shell nanoparticles assembled thin coatings by matrix assisted pulsed laser evaporation for antibacterial drug-targeted delivery. Magnetite nanoparticles have been synthesized and subsequently characterized by transmission electron microscopy and x-ray diffraction. The obtained thin coatings have been investigated by FTIR and scanning electron microscope, and tested by in vitro biological assays, for their influence on in vitro bacterial biofilm development and cytotoxicity on human epidermoid carcinoma (HEp2) cells. PMID:25797361
Grumezescu, A M; Cristescu, R; Chifiriuc, M C; Dorcioman, G; Socol, G; Mihailescu, I N; Mihaiescu, D E; Ficai, A; Vasile, O R; Enculescu, M; Chrisey, D B
Antibacterial Activity of Pepducins, Allosterical Modulators of Formyl Peptide Receptor Signaling
Pepducins containing a fatty acid linked to an amino acid sequence derived from cytosolic parts of a G-protein-coupled receptor (GPCR) constitute a new group of lipopeptide tools in GPCR studies. Pepducins corresponding to the third intracellular loop of formyl peptide receptor 2 (FPR2) activate human neutrophils, and we show here that, in addition, these allosteric modulators of receptor activity also kill bacteria. The functional dualism of FPR2 pepducins could potentially be explored as a novel class of antibacterial drugs with immunomodulatory properties. PMID:24590483
Winther, Malene; Gabl, Michael; Oprea, Tudor I.; J÷nsson, Bodil; Boulay, Francois; Bylund, Johan; Dahlgren, Claes
Antituberculosis drug research: a critical overview.
The increasing drug resistance of Mycobacterium tuberculosis to the currently used drugs and HIV coinfection has caused alarm in the international scientific community. Subsequently, there is an urgent need for the development of new drug molecules with newer targets and with an alternative mechanism of action. Since the last 50 years, the same long-duration, multidrug treatment plan is being followed for the treatment of tuberculosis. The objective of this review article is to critically analyze the antitubercular potential of various classes of compounds (quinoline, diamine, quinolone, fluoroquinolone, quinone, nitroimidazole, terpenoid, isonicotinyl, oxazolidinone, pyrimidine, and purine), their possibility to be a future drug candidate, and latest information on the clinical status of some novel antitubercular compounds. Compounds such as moxifloxacin, PA824, and TMC207 are well tolerated and there is no adverse effect shown by them. Moxifloxacin and gatifloxacin shows cross-resistance to the currently used drugs while no cross-resistance observed in case of TMC207 and PA824. Some compounds like OPC67683 and PA824 are bactericidal in nature. PMID:22622957
Beena; Rawat, Diwan S
Antibacterial activity of traditional medicinal plants used by Haudenosaunee peoples of New York State
Background The evolution and spread of antibiotic resistance, as well as the evolution of new strains of disease causing agents, is of great concern to the global health community. Our ability to effectively treat disease is dependent on the development of new pharmaceuticals, and one potential source of novel drugs is traditional medicine. This study explores the antibacterial properties of plants used in Haudenosaunee traditional medicine. We tested the hypothesis that extracts from Haudenosaunee medicinal plants used to treat symptoms often caused by bacterial infection would show antibacterial properties in laboratory assays, and that these extracts would be more effective against moderately virulent bacteria than less virulent bacteria. Methods After identification and harvesting, a total of 57 different aqueous extractions were made from 15 plant species. Nine plant species were used in Haudenosaunee medicines and six plant species, of which three are native to the region and three are introduced, were not used in traditional medicine. Antibacterial activity against mostly avirulent (Escherichia coli, Streptococcus lactis) and moderately virulent (Salmonella typhimurium, Staphylococcus aureus) microbes was inferred through replicate disc diffusion assays; and observed and statistically predicted MIC values were determined through replicate serial dilution assays. Results Although there was not complete concordance between the traditional use of Haudenosaunee medicinal plants and antibacterial activity, our data support the hypothesis that the selection and use of these plants to treat disease was not random. In particular, four plant species exhibited antimicrobial properties as expected (Achillea millefolium, Ipomoea pandurata, Hieracium pilosella, and Solidago canadensis), with particularly strong effectiveness against S. typhimurium. In addition, extractions from two of the introduced species (Hesperis matronalis and Rosa multiflora) were effective against this pathogen. Conclusions Our data suggest that further screening of plants used in traditional Haudenosaunee medicine is warranted, and we put forward several species for further investigation of activity against S. typhimurium (A. millefolium, H. matronalis, I. pandurata, H. pilosella, R. multiflora, S. canadensis). PMID:21054887
A simple method for primary screening of antibacterial peptides in plant seeds
Background and Objectives Regarding the importance of finding new antibacterial drugs, screening of plants as a promising resource are now conducted worldwide. In this study, we report the application of a simple previously described method for screening of different plant seeds in order to find the best resources of plant antimicrobial peptides. Materials and Methods Total water soluble protein of 10 different plant seeds were extracted and subjected to SDS-PAGE and subsequent agar-overlay bioassays. Standard strains of Staphylococcus aureus, Enterococcus faecium and Escherichia coli were included in the bioassays. This method also was used for total proteins precipitated by Ammonium sulphate which ensure the protein nature of the test substances. Molecular size and the amounts of effective peptides were estimated using Tricin-SDS-PAGE and densitometry. Results Two different plant seeds showed noticeable antibacterial activities against tested Gram positive bacteria and a moderate inhibitory effect on Gram negative ones. Based on the results of Tricin-SDS-PAGE analysis which were carried out in parallel to bioassays, it was concluded that effective antibacterial substances are peptides with molecular weight of slightly larger than 5 kDa. Conclusion On the basis of results of agar-overlay experiments and by screening of 10 different herbal seeds, we could introduce seeds of M. sativa L. and Onobrychis sativa Lam., as great sources of putative plant antibacterial peptides. The proposed screening method can be used for screening of large number of different plant seeds and even other parts of the plant body, regarding some necessary modification in total water soluble protein extraction steps. PMID:22347591
Aliahmadi, A; Roghanian, R; Emtiazi, G; Ghassempour, A
Biotransformation of the antibiotic agent flumequine by ligninolytic fungi and residual antibacterial activity of the transformation mixtures.
Flumequine, a fluoroquinolone antibiotic, is applied preferably in veterinary medicine, for stock breeding and treatment of aquacultures. Formation of drug resistance is a matter of general concern when antibiotics such as flumquine occur in the environment. Thus, biodegradation of flumequine in solution was investigated using five different ligninolytic fungi. Irpex lacteus, Dichomitus squalens, and Trametes versicolor proved most efficient and transformed more than 90% of flumequine within 6 or even 3 days. Panus tigrinus and Pleurotus ostreatus required up to 14 days to remove >90% of flumequine. Analyses of the metabolites by liquid chromatography-mass spectrometry suggest different transformation pathways for the different fungal strains. Structure proposals were elaborated for 8 metabolites. 7-Hydroxy-flumequine and flumequine ethyl ester were identified as common metabolites produced by all ligninolytic fungi. The largest variety of metabolites was formed by D. squalens. Residual antibacterial activity of the metabolite mixtures was tested using gram-positive and gram-negative bacteria. While for the less efficient P. tigrinus and P. ostreatus cultures the antibacterial activities corresponded to the residual concentrations of flumequine, a remarkable antibacterial activity remained in the D. squalens cultures although flumequine was transformed to more than 90%. Obviously, antibacterially active transformation products were formed by this fungal strain. PMID:24261869
Cvan?arovß, Monika; Moeder, Monika; Filipovß, Alena; Reemtsma, Thorsten; Cajthaml, TomßÜ
Antibacterial activity against ?- lactamase producing Methicillin and Ampicillin-resistants Staphylococcus aureus: fractional Inhibitory Concentration Index (FICI) determination
Background The present study reports the antibacterial capacity of alkaloid compounds in combination with Methicillin and Ampicillin-resistants bacteria isolated from clinical samples. The resistance of different bacteria strains to the current antibacterial agents, their toxicity and the cost of the treatment have led to the development of natural products against the bacteria resistant infections when applied in combination with conventional antimicrobial drugs. Method The antibacterial assays in this study were performed by using inhibition zone diameters, MIC, MBC methods, the time-kill assay and the Fractional Inhibitory Concentration Index (FICI) determination. On the whole, fifteen Gram-positive bacterial strains (MRSA/ARSA) were used. Negative control was prepared using discs impregnated with 10 % DMSO in water and commercially available Methicillin and Ampicillin from Alkom Laboratories LTD were used as positive reference standards for all bacterial strains. Results We noticed that the highest activities were founded with the combination of alkaloid compounds and conventional antibiotics against all bacteria strains. Then, results showed that after 7 h exposition there was no viable microorganism in the initial inoculums. Conclusion The results of this study showed that alkaloid compounds in combination with conventional antibiotics (Methicillin, Ampicillin) exhibited antimicrobial effects against microorganisms tested. These results validate the ethno-botanical use of Cienfuegosia digitata Cav. (Malvaceae) in Burkina Faso. Moreover, this study demonstrates the potential of this herbaceous as a source of antibacterial agent that could be effectively used for future health care purposes. PMID:22716026
Safety considerations of fluoroquinolones in the elderly: an update.
The fluoroquinolones ciprofloxacin, levofloxacin, moxifloxacin and gemifloxacin are widely used for the treatment of various types of bacterial infections. Overall, these antibacterial agents can be considered safe and well tolerated drugs. Comparative studies have evaluated the use of quinolones in elderly and younger populations. Although age per se does not seem to decrease their tolerability, specific adverse effects of the quinolones must be considered when they are chosen for antibacterial treatment. Renal function declines consistently with age and doses of renally excreted quinolones (e.g. ofloxacin, levofloxacin, gatifloxacin) need to be adjusted if a clinically relevant reduction of creatinine clearance is identified. Reactions of the gastrointestinal tract, such as nausea, dyspepsia, vomiting or diarrhoea, are among the most often registered adverse drug reactions during therapy with fluoroquinolones. Treatment with a quinolone causes diarrhoea less frequently than treatment with other classes of antimicrobials. Conflicting data have been published with respect to the incidence of Clostridium difficile-associated diarrhoea in quinolone-treated patients. Hypersensitivity reactions, often manifested on the skin, occur less commonly during therapy with quinolones than, for example, during therapy with beta-lactam antibacterials. Adverse reactions of the CNS are of particular concern in the elderly population. Given the CNS excitatory effects of quinolones, elderly patients should be monitored carefully for such symptoms. It is likely that many signs of possible adverse reactions, such as confusion, weakness, loss of appetite, tremor or depression, are often mistakenly attributed to old age and remain unreported. Quinolones should be used with caution in patients with known or suspected CNS disorders that predispose to seizures (e.g. severe cerebral arteriosclerosis or epilepsy). Quinolones can cause QT interval prolongation. They should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalaemia or hypomagnesaemia and patients receiving class IA (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents. Tendinitis and tendon ruptures are recognized as quinolone-induced adverse effects that can occur during treatment or as late as several months after treatment. Chronic renal diseases, concomitant use of corticosteroids and age >60 years are known risk factors for quinolone-induced tendopathies. Overall, the specific adverse-effect profile of quinolones must be considered when they are chosen for treatment of bacterial infections. Because of physiological changes in renal function and when certain co-morbidities are present, some special considerations are necessary when elderly patients are treated with these drugs. PMID:20210367
Stahlmann, Ralf; Lode, Hartmut
Geographical epidemiology of antibacterials in the preschool age
Abstract Background Thematic maps allow a more rapid and immediate reading of the geographical differences in the distribution of data referred to a specific territory. The aim of this study was to show, for the first time, the application of some statistical and cartographic tools in the analysis of drug utilization in the pediatric population of an Italian region, and to assess the intra-regional difference in the antibiotic prescriptions. Methods To assess the type of geographic distribution of the prescriptions, the analyses were based on the standardized prevalence rate (z-score) calculated at the local health unit, health district, and municipality levels. PearsonÆs coefficient of correlation was used to evaluate the correlation with hospitalization and the MoranÆs I index was used to evaluate the existence of spatial autocorrelation. With the use of Getis-OrdÆs G statistic, clusters of areas with high and low levels of prevalence were identified and mapped. The probability of receiving at least one prescription of antibacterials during the year for all the children included in the study was evaluated with a logistic regression model. Results With the use of the maps it was possible to see that the prescriptions were not correlated with the health status of the population, but with the tendency of the pediatrician to prescribe drugs. This was also confirmed by the logistic regression model constructed to estimate the probability of receiving at least one prescription of antibacterials considering, as independent variables: age, sex, prevalence of hospitalizations in the district of residence, prescriptive attitude of the pediatrician, sex of the pediatrician, pediatricianÆs age group, and duration of the pediatricianÆs contract with the local health unit (LHU). Conclusions The priority actions to rationalize the use of antibacterials in the preschool age should concentrate on the active participation of the pediatricians in permanent education activities. Moreover, the competent authorities should increasing their efforts to limit unnecessary prescriptions and increase appropriateness of prescribing. Riassunto Introduzione Le mappe tematiche consentono una pi∙ rapida ed immediata lettura delle differenze geografiche nella distribuzione di dati riferiti ad un territorio specifico. Lo scopo dello studio Ķ mostrare, per la prima volta, lÆapplicazione di alcuni strumenti statistici e cartografici, nellÆanalisi dellÆuso dei farmaci nella popolazione pediatrica di una regione italiana e valutare le differenze intra-regionali. Metodi Per valutare il tipo di distribuzione geografica delle prescrizioni, sono stati calcolati i tassi di prevalenza standardizzati (punteggi-z) a livello di ASL, Distretti Sanitari e Comuni. Per valutare la correlazione con le ospedalizzazioni Ķ stato usato il coefficiente di correlazione di Pearson; per valutare lÆesistenza di autocorrelazione spaziale Ķ stato usato lÆindice I di Moran. Tramite lÆuso della statistica G di Getis-Ord sono stati identificati cluster di aree ad alto e basso livello di prevalenza. Infine con un modello di regressione logistica Ķ stata stimata la probabilitÓ di ricevere almeno una prescrizione nel corso dellÆanno per tutti i pazienti inclusi nello studio. Risultati Con lÆuso delle mappe Ķ possibile vedere che le prescrizioni non sono correlate con lo stato di salute della popolazione, ma sono correlate con lÆattitudine prescrittiva del pediatra. Questo Ķ confermato anche dal modello di regressione logistica costruito per stimare la probabilitÓ di ricevere almeno una prescrizione considerando come variabili indipendenti lÆetÓ, il sesso, la prevalenza di ricoveri nel distretto di residenza, lÆattitudine prescrittiva del pediatra, la classe di etÓ del pediatra e la durata della convenzione del pediatra con lÆAzienda Sanitaria Locale (ASL). Conclusioni Gli interventi primari per razionalizzare lȁ
Lactococcus garvieae carries a chromosomally encoded pentapeptide repeat protein that confers reduced susceptibility to quinolones in Escherichia coli producing a cytotoxic effect.
This study characterises a chromosomal gene of Lactococcus garvieae encoding a pentapeptide repeat protein designated as LgaQnr. This gene has been implicated in reduced susceptibility to quinolones in this bacterium, which is of relevance to both veterinary and human medicine. All of the L. garvieae isolates analysed were positive for the lgaqnr gene. The expression of lgaqnr in Escherichia coli reduced the susceptibility to quinolones, producing an adverse effect. The reduced susceptibility to ciprofloxacin was 16-fold in E. coli ATCC 25922 and 32-fold in E. coli DH10B, compared to the control strains. The minimum inhibitory concentration of nalidixic acid was also increased 4 or 5-fold. The effect of the expression of lgaqnr in E. coli was investigated by electron microscopy and was observed to affect the structure of the cell and the inner membrane of the recombinant cells. PMID:24965125
Gibello, Alicia; DĒaz de Alba, Paula; Blanco, M Mar; Machuca, Jesus; Cutuli, M Teresa; RodrĒguez-MartĒnez, Josķ Manuel
Design, synthesis and in vitro antibacterial activity of 7-(4-alkoxyimino-3-aminomethylpiperidin-1-yl)fluoroquinolone derivatives.
We report herein the design and synthesis of novel 7-(4-alkoxyimino-3-aminomethylpiperidin-1-yl) fluoroquinolone derivatives. The antibacterial activity of the newly synthesized compounds was evaluated and compared with gemifloxacin, levofloxacin and ciprofloxacin. Results reveal that compounds 10, 16, and 17 have good activity against all of the tested gram-positive organisms including drug-resistance strains (MICs: 0.125-4 ?g/mL). In addition, compounds 16 and 17 (MICs: 4 ?g/mL) were 2- to 8-fold more potent than the reference drugs against Pseudomonas aeruginosa. PMID:21515052
Chai, Yun; Wang, Jian; Liu, Mingliang; Yi, Hong; Sun, Lanying; You, Xuefu; Guo, Huiyuan
Determination of quinolones and fluoroquinolones in fish tissue and seafood by high-performance liquid chromatography with electrospray ionisation tandem mass spectrometric detection
A reversed-phase high-performance liquid chromatographic method with tandem mass-spectrometric detection was developed and validated for the simultaneous analysis of eight quinolones and fluoroquinolones (oxolinic acid, flumequine, piromidic acid, enrofloxacin, ciprofloxacin, danofloxacin, sarafloxacin and orbifloxacin) in trout tissue, prawns and abalone. The analytes were extracted from homogenised tissue using acetonitrile and the extracts subjected to an automated two-stage solid-phase extraction process
Lesley Johnston; Lindsey Mackay; Meg Croft
Plasmid-Mediated Quinolone Resistance Genes and Antibiotic Residues in Wastewater and Soil Adjacent to Swine Feedlots: Potential Transfer to Agricultural Lands
Background: Inappropriate use of antibiotics in swine feed could cause accelerated emergence of antibiotic resistance genes, and agricultural application of swine waste could spread antibiotic resistance genes to the surrounding environment. Objectives: We investigated the distribution of plasmid-mediated quinolone resistance (PMQR) genes from swine feedlots and their surrounding environment. Methods: We used a culture-independent method to identify PMQR genes and estimate their levels in wastewater from seven swine feedlot operations and corresponding wastewater-irrigated farm fields. Concentrations of (fluoro)quinolones in wastewater and soil samples were determined by ultra-performance liquid chromatography¢electrospray tandem mass spectrometry. Results: The predominant PMQR genes in both the wastewater and soil samples were qnrD, qepA, and oqxB, whereas qnrS and oqxA were present only in wastewater samples. Absolute concentrations of all PMQR genes combined ranged from 1.66 ū 107 to 4.06 ū 108 copies/mL in wastewater and 4.06 ū 106 to 9.52 ū 107 copies/g in soil. Concentrations of (fluoro)quinolones ranged from 4.57 to 321 ng/mL in wastewater and below detection limit to 23.4 ng/g in soil. Significant correlations were found between the relative abundance of PMQR genes and (fluoro)quinolone concentrations (r = 0.71, p = 0.005) and the relative abundance of PMQR genes in paired wastewater and agricultural soil samples (r = 0.91, p = 0.005). Conclusions: Swine feedlot wastewater may be a source of PMQR genes that could facilitate the spread of antibiotic resistance. To our knowledge, this is the first study to examine the occurrence of PMQR genes in animal husbandry environments using a culture-independent method. PMID:22569244
Li, Juan; Wang, Thanh; Shao, Bing; Shen, Jianzhong; Wang, Shaochen
The Real Practice of Antibiotic Prophylaxis for Prostate Biopsy in Korea Where the Prevalence of Quinolone-Resistant Escherichia coli Is High
Purpose Transrectal ultrasonography-guided prostate biopsy (TRUS-Bx) is an essential procedure for diagnosing prostate cancer. The American Urological Association (AUA) Guideline recommends fluoroquinolone alone for 1 day during TRUS-Bx. However, this recommendation may not be appropriate in regions where the prevalence of quinolone-resistant Escherichia coli is high. We investigated the real practice of antibiotic prophylaxis for TRUS-Bx in Korea. Materials and Methods A total of 77 hospitals performing TRUS-Bx were identified and an e-mail was sent to the Urology Department of those hospitals. The questions in the e-mail included the choice of antibiotics before and after the procedure and the duration of antibiotic therapy after TRUS-Bx. Results A total of 54 hospitals (70.0%) responded to the e-mail. Before TRUS-Bx, all hospitals administered intravenous antibiotic prophylaxis. The percentage of hospitals that used quinolone, cephalosporin, and aminoglycoside alone was 48.1%, 20.4%, and 9.3%, respectively. The percentage of hospitals that used two or more antibiotics was 22.2%. After biopsy, all 54 hospitals prescribed oral antibiotics. The percentage of hospitals that prescribed quinolone alone, cephalosporin alone, or a combination of two or more antibiotics was 77.8%, 20.4%, and 1.8%, respectively. The duration of antibiotic use was more than 3 days in most hospitals (79.6%). Only four hospitals (7.4%) followed the AUA recommendation of a 1-day regimen. Conclusions The AUA recommendation was not followed by most hospitals in Korea. This clinical behavior might reflect the high quinolone resistance rate in Korea, and further studies on the most efficient prophylactic antibiotics after TRUS-Bx in Korea are warranted. PMID:25237461
Kim, Dae Hyun; Bae, Sang Rak; Choi, Woo Suk; Paick, Sung Hyun; Kim, Hyeong Gon; Loh, Yong Soo
Insights through AM1 calculations into the structural requirement of 3,4,6-substituted-2-quinolone analogs towards FMS kinase inhibitory activity
In the present work, we focused on quantification of activity of 3,4,6-substituted-2-quinolone derivatives with reference to structural properties. The multi-variant regression expressions were developed through sequential multiple linear regression technique, considering adjustable correlation coefficient (radj2). The amalgamated best fit consensus scoring function showed coefficient of determination (0.891), leave one out cross validated squared correlation coefficient (0.776) and external predictivity value
Arun Kumar Gupta; Neetu Sabarwal; Yogesh P. Agrawal; Sumeet Prachand; Sanjay Jain
Tricyclic GyrB/ParE (TriBE) inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents.
Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models. PMID:24386374
Tari, Leslie W; Li, Xiaoming; Trzoss, Michael; Bensen, Daniel C; Chen, Zhiyong; Lam, Thanh; Zhang, Junhu; Lee, Suk Joong; Hough, Grayson; Phillipson, Doug; Akers-Rodriguez, Suzanne; Cunningham, Mark L; Kwan, Bryan P; Nelson, Kirk J; Castellano, Amanda; Locke, Jeff B; Brown-Driver, Vickie; Murphy, Timothy M; Ong, Voon S; Pillar, Chris M; Shinabarger, Dean L; Nix, Jay; Lightstone, Felice C; Wong, Sergio E; Nguyen, Toan B; Shaw, Karen J; Finn, John
Screening seeds of Scottish plants for antibacterial activity
Based on ethnopharmacological and taxonomic information, seeds of 21 Scottish plant species from 14 different families were obtained from authentic seed suppliers. Their n-hexane, dichloromethane and methanol extracts were assessed for antibacterial activity against 11 pathogenic bacterial species. Methanol extracts of 11 plant species showed significant antibacterial activity. Malva moschata and Prunus padus were active against five bacterial species, Reseda
Yashodharan Kumarasamy; Philip John Cox; Marcel Jaspars; Lutfun Nahar; Satyajit Dey Sarker
Antibacterial Activity of Leptadenia reticulata (Retz.) Wight. & Arn. (Asclepidaceae).
Leptadenia reticulata of Asclepidaceae family is a shrub, originally property of Petroleum ether, Alcohol & Chloroform extract of L. reticulata. The antimicrobial testing was carried out by "Disc diffusion method". Amongst the tested three extracts, chloroform extract showed high antimicrobial activity against E. coli, alcoholic extract showed high antibacterial activity against Pseudomonas aeruginosa, while Petroleum ether extract showed antibacterial activity against Klebsilla pneumonae. PMID:22557325
Kalidass, C; Glory, M; Borgio, Francis; Manickam, V S
Antibacterial Activity of Leptadenia reticulata (Retz.) Wight. & Arn. (Asclepidaceae)
Leptadenia reticulata of Asclepidaceae family is a shrub, originally property of Petroleum ether, Alcohol & Chloroform extract of L. reticulata. The antimicrobial testing was carried out by ōDisc diffusion methodö. Amongst the tested three extracts, chloroform extract showed high antimicrobial activity against E. coli, alcoholic extract showed high antibacterial activity against Pseudomonas aeruginosa, while Petroleum ether extract showed antibacterial activity against Klebsilla pneumonae PMID:22557325
Kalidass, C.; Glory, M.; Borgio, Francis; Manickam, V S
Antibacterial activity of northern Ontario medicinal plant extracts
Antibacterial activity of northern Ontario medicinal plant extracts Haider M. Hassan1 , Zi. and Qin, W. 2014. Antibacterial activity of northern Ontario medicinal plant extracts. Can. J. Plant Sci strumarium L. medicinal plants was analyzed through the hole-plate diffusion, minimum inhibitory
Qin, Wensheng
Screening of some Palestinian medicinal plants for antibacterial activity
Antibacterial activity of organic and aqueous extracts of 15 Palestinian medicinal plants were carried against eight different species of bacteria: Bacillus subtilis, two Escherichia coli species, Staphylococcus aureus (methicillin resistant), two S. aureus (methicillin sensitive) species, Pseudomonas aeruginosa, and Enterococcus fecalis. Of the 15 plants tested, eight showed antibacterial activity. Each plant species has unique against different bacteria. The most
T Essawi; M Srour
Screening of Yemeni medicinal plants for antibacterial and cytotoxic activities
Ethanolic extracts of 20 selected plant species used by Yemeni traditional healers to treat infectious diseases were screened for their antibacterial activity against both Gram-positive and Gram-negative bacteria, as well as for cytotoxic activity. Fourteen of the ethanolic extracts showed variable degrees of antibacterial activity. The active ethanolic extracts were partitioned between ethyl acetate and water for a first separation.
N. A. Awadh Ali; W.-D J³lich; C Kusnick; U Lindequist
Antibacterial effect of essential oils and interaction with food components
The antibacterial effect of essential oils (EOs) derived from Citrus lemon, Juniperus communis, Origanum majorana, and Salvia sclarea, was investigated either alone or in combination, on 2 food related bacteria (Bacillus cereus and Escherichia coli). The influence of food ingredients Ś hydrolyzed proteins originating from animal and plant (meat extract and soy peptone)\\u000a and sucrose Ś on the antibacterial effect
Rentsenkhand Tserennadmid; Mikl¾s Tak¾; Lßszl¾ Galg¾czy; Tamßs Papp; Csaba Vßgv÷lgyi; Lßszl¾ Ger?; Judit Krisch
Synthesis and characterization of antibacterial dental monomers and composites
The objective of this study is to synthesize antibacterial methacrylate and methacrylamide monomers and formulate antibacterial fluoride-releasing dental composites. Three antibacterial methacrylate or methacrylamide monomers containing long-chain quaternary ammonium fluoride, 1,2-methacrylamido-N,N,N-trimethyldodecan-1-aminium fluoride (monomer I), N-benzyl-11-(methacryloyloxy)-N,N-dimethylundecan-1-aminium fluoride (monomer II), and methacryloxyldecylpyridinium fluoride (monomer III) have been synthesized and analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The cytotoxicity test and bactericidal test against Streptococcus mutans indicate that antibacterial monomer II is superior to monomers I and III. A series of dental composites containing 0¢6% of antibacterial monomer II have been formulated and tested for degree of conversion (DC), flexure strength, water sorption, solubility, and inhibition of S. mutans biofilms. An antibacterial fluoride-releasing dental composite has also been formulated and tested for flexure strength and fluoride release. The dental composite containing 3% of monomer II has a significant effect against S. mutans biofilm formation without major adverse effects on its physical and mechanical properties. The new antibacterial monomers can be used together with the fluoride-releasing monomers containing a ternary zirconiun- fluoride chelate to formulate a new antibacterial fluoride- releasing dental composite. Such a new dental composite is expected to have higher anticaries efficacy and longer service life. PMID:22447582
Xu, Xiaoming; Wang, Yapin; Liao, Sumei; Wen, Zezhang T.; Fan, Yuwei
Methyl carnosate, an antibacterial diterpene isolated from Salvia officinalis leaves.
Ethanolic extracts of Salvia officinalis leaves demonstrated antibacterial activity against Bacillus cereus. Fractionation of the extracts led to the isolation of the most active antibacterial compound, which, from spectroscopic and LC-MS evidence, was proved to be the diterpene, methyl carnosate. PMID:23738442
Climati, Elisa; Mastrogiovanni, Fabio; Valeri, Maria; Salvini, Laura; Bonechi, Claudia; Mamadalieva, Nilufar Zokirzhonovna; Egamberdieva, Dilfuza; Taddei, Anna Rita; Tiezzi, Antonio
Technology Transfer Automated Retrieval System (TEKTRAN)
The AATCC Test Method 100-1999,"Antibacterial Finishes on Textile Materials: Assessment of", was adapted to the resources available to our laboratory in order to measure the antimicrobial properties of fabric made from flax and cotton blends. The general method for assessing the antibacterial tende...
Flame retardant antibacterial cotton high-loft nonwoven fabrics
Technology Transfer Automated Retrieval System (TEKTRAN)
Flame retardant treated gray cotton fibers were blended with antibacterial treated gray cotton fibers and polyester/polyester sheath/core bicomponent fibers to form high-loft fabrics. The high flame retardancy (FR) and antibacterial property of these high lofts were evaluated by limiting oxygen inde...
Antibacterial nanostructured composite films for biomedical applications: microstructural characteristics, biocompatibility, and antibacterial mechanisms.
Hydrogenated Cu-incorporated diamond-like carbon (a-C:H/Cu) films were prepared in the present study using a radio-frequency plasma magnetron sputtering system at various CH4/Ar gas ratios. The a-C:H/Cu films were characterized by scanning electron microscopy, atomic force microscopy, Raman spectroscopy, transmission electron microscopy, nano-indentation and a contact angle goniometer. The antibacterial properties and cell cytotoxicity of a-C:H/Cu films were evaluated as per JIS Z2801:2010 and ISO 10993-5 specifications, respectively. The analytical results revealed that the production of a-C:H/Cu films varied with the CH4/Ar ratio, and the phase transformation (amorphous-like ? nano-polycrystalline structure) was induced by Cu doping/ion bombardment and radical reactions. Moreover, it was found that the microhardness of the a-C:H/Cu films decreased with increasing Ar fraction in the gas ratio. The a-C:H/Cu films exhibited a high hydrophobic surface feature. The film which contained 77.3 ?▒ ?4.4 at.% Cu did not influence cell adhesion and proliferation behaviors. Antibacterial tests also demonstrated that a-C:H/Cu films possessed excellent antibacterial properties. Therefore, a-C:H/Cu films could be developed as promising antibacterial coatings for biomedical applications. PMID:23528126
Lee, Fei-Peng; Wang, Da-Yen; Wang, Duen-Jeng; Chen, Li-Kai; Kung, Chun-Ming; Wu, Yi-Chien; Ou, Keng-Liang; Yu, Chih-Hua
The impact of genomics on novel antibacterial targets.
Antibiotic discovery has remained primarily focused on improving versions of existing classes of antibiotics which work on a limited set of bacterial targets. In addition, the characterization of these targets has focused almost entirely on Escherichia coli homologs. The advancing problems associated with resistant pathogens has driven a critical need for the discovery of new classes of antibiotics which will target novel bacterial functions required for viability and pathogenicity. Recent advances in DNA sequencing technology have now made it possible to elucidate the entire genomes of pathogenic bacteria. Comparative analysis of these genome sequences, driven by advancements in the availability of bioinformatic tools, is dramatically increasing our ability to interrogate the spectrum and selectivity of novel antibacterial target areas. In this review, we present an update on the antibiotic target areas of tRNA synthetases, two-component signal transduction systems, peptidoglycan biosynthesis, fatty acid biosynthesis and chorismate biosynthesis. We illustrate how the availability of genomes from a range of clinically important pathogens has enabled valid considerations of the limitations and advantages of particular targets based on their predicted spectrum and selectivity. Furthermore, we demonstrate how genomics is facilitating the characterization of targets from relevant pathogens and how these data, coupled with genomic-based technologies, provide new approaches for drug discovery. PMID:19649849
Payne, D J; Wallis, N G; Gentry, D R; Rosenberg, M
Association of Transferable Quinolone Resistance Determinant qnrB19 with Extended-Spectrum ?-Lactamases in Salmonella Give and Salmonella Heidelberg in Venezuela
Four nontyphoidal Salmonella strains with resistance to extended-spectrum cephalosporins and nonclassical quinolone resistance phenotype were studied. Two S. Give were isolated from pediatric patients with acute gastroenteritis, and two S. Heidelberg were recovered from raw chicken meat. Phenotypic characterization included antimicrobial susceptibility testing and detection of extended-spectrum ?-lactamases (ESBLs) by the double-disc synergy method. The detection of quinolone resistance-determining regions (QRDR) of gyrA, gyrB, and gyrC genes, blaESBLs genes, and plasmid-mediated quinolone resistance (PMQR) determinants was carried out by molecular methods. Plasmid analysis included Southern blot and restriction patterns. Transferability of resistance genes was examined by transformation. blaTEM-1 + blaSHV-12 genes were detected in S. Give SG9611 and blaTEM-1 + blaCTX-M-2 in the other three strains: S. Give SG9811, S. Heidelberg SH7511, and SH7911. Regardless of origin and serovars, the qnrB19 gene was detected in the 4 strains studied. All determinants of resistance were localized in plasmids and successfully transferred by transformation. This study highlights the circulation of qnrB19 associated with blaTEM-1, blaSHV-12, and blaCTX-M-2 in S. Give and S. Heidelberg in Venezuela. The recognition of factors associated with increasing resistance and the study of the molecular mechanisms involved can lead to a more focused use of antimicrobial agents. PMID:24187555
Gonzßlez, Fanny
Reduced phototoxicity of a fluoroquinolone antibacterial agent with a methoxy group at the 8 position in mice irradiated with long-wavelength UV light.
A newly developed fluoroquinoline, Q-35 (8-OCH3), in which a methoxy group was substituted at the 8 position of the quinoline nucleus, was very stable under irradiation with long-wave UV light (UVA). Derivatives, a fluoroquinolone with no substitution (the 8-H analog) and one in which a fluorine was substituted (the 8-F analog), were degraded in their solutions by the UVA irradiation. The phototoxic inducibility by these derivatives was further studied in a murine model. When mice were dosed orally with 800 mg of Q-35 (8-OCH3) per kg of body weight, the maximum dose given, and exposed to the UVA light, no inflammatory lesions were observed in their ears. Ear redness was marked in mice given more than 12.5 mg of the 8-F analog or 200 mg of the 8-H analog per kg. Histopathological changes, edema, and infiltration of neutrophils were also observed microscopically in groups receiving the 8-H or 8-F analog but not in groups receiving Q-35 (8-OCH3). Similar inflammatory reactions were observed to occur in a dose-dependent manner with other available fluoroquinolone antibacterial agents such as lomefloxacin, enoxacin, norfloxacin, ciprofloxacin and ofloxacin. These results suggest that the introduction of a methoxy group at the 8 position of the quinolone nucleus is important for the reduction of phototoxicity. PMID:8257147
Marutani, K; Matsumoto, M; Otabe, Y; Nagamuta, M; Tanaka, K; Miyoshi, A; Hasegawa, T; Nagano, H; Matsubara, S; Kamide, R
Reduced phototoxicity of a fluoroquinolone antibacterial agent with a methoxy group at the 8 position in mice irradiated with long-wavelength UV light.
A newly developed fluoroquinoline, Q-35 (8-OCH3), in which a methoxy group was substituted at the 8 position of the quinoline nucleus, was very stable under irradiation with long-wave UV light (UVA). Derivatives, a fluoroquinolone with no substitution (the 8-H analog) and one in which a fluorine was substituted (the 8-F analog), were degraded in their solutions by the UVA irradiation. The phototoxic inducibility by these derivatives was further studied in a murine model. When mice were dosed orally with 800 mg of Q-35 (8-OCH3) per kg of body weight, the maximum dose given, and exposed to the UVA light, no inflammatory lesions were observed in their ears. Ear redness was marked in mice given more than 12.5 mg of the 8-F analog or 200 mg of the 8-H analog per kg. Histopathological changes, edema, and infiltration of neutrophils were also observed microscopically in groups receiving the 8-H or 8-F analog but not in groups receiving Q-35 (8-OCH3). Similar inflammatory reactions were observed to occur in a dose-dependent manner with other available fluoroquinolone antibacterial agents such as lomefloxacin, enoxacin, norfloxacin, ciprofloxacin and ofloxacin. These results suggest that the introduction of a methoxy group at the 8 position of the quinolone nucleus is important for the reduction of phototoxicity. Images PMID:8257147
Marutani, K; Matsumoto, M; Otabe, Y; Nagamuta, M; Tanaka, K; Miyoshi, A; Hasegawa, T; Nagano, H; Matsubara, S; Kamide, R
In Vitro Antibacterial Activity of Essential Oils against Streptococcus pyogenes.
Streptococcus pyogenes plays an important role in the pathogenesis of tonsillitis. The present study was conducted to evaluate the in vitro antibacterial activities of 18 essential oils chemotypes from aromatic medicinal plants against S. pyogenes. Antibacterial activity of essential oils was investigated using disc diffusion method. Minimum Inhibitory Concentration of essential oils showing an important antibacterial activity was measured using broth dilution method. Out of 18 essential oils tested, 14 showed antibacterial activity against S. pyogenes. Among them Cinnamomum verum, Cymbopogon citratus, Thymus vulgaris CT thymol, Origanum compactum, and Satureja montana essential oils exhibited significant antibacterial activity. The in vitro results reported here suggest that, for patients suffering from bacterial throat infections, if aromatherapy is used, these essential oils, considered as potential antimicrobial agents, should be preferred. PMID:23662123
Sfeir, Julien; Lefranńois, Corinne; Baudoux, Dominique; Derbrķ, Sķverine; Licznar, Patricia
In Vitro Antibacterial Activity of Essential Oils against Streptococcus pyogenes
Streptococcus pyogenes plays an important role in the pathogenesis of tonsillitis. The present study was conducted to evaluate the in vitro antibacterial activities of 18 essential oils chemotypes from aromatic medicinal plants against S. pyogenes. Antibacterial activity of essential oils was investigated using disc diffusion method. Minimum Inhibitory Concentration of essential oils showing an important antibacterial activity was measured using broth dilution method. Out of 18 essential oils tested, 14 showed antibacterial activity against S. pyogenes. Among them Cinnamomum verum, Cymbopogon citratus, Thymus vulgaris CT thymol, Origanum compactum, and Satureja montana essential oils exhibited significant antibacterial activity. The in vitro results reported here suggest that, for patients suffering from bacterial throat infections, if aromatherapy is used, these essential oils, considered as potential antimicrobial agents, should be preferred. PMID:23662123
Sfeir, Julien; Lefranńois, Corinne; Baudoux, Dominique; Derbrķ, Sķverine; Licznar, Patricia
Terrestrial actinomycetes from diverse locations of Uttarakhnad, India: Isolation and screening for their antibacterial activity
Background and Objective Uttarakhand region is less explored, but possess a great biodiversity. This diversity can be explored for isolation and characterization of new actinomycetes strains for seeking antimicrobial molecules. It can therefore be predicted that novel bioactive metabolite producing actinomycetes can be discovered to combat multidrug resistant bacterial pathogens. Materials and Methods Variations in the viable count of actinomycetes were accessed in different altitudes. Actinomycetes were isolated, indentified and screened for their antibacterial activity. Results The highest viable counts of actinomycetes were recorded in valleys followed by mid hills and high hills. A total of 512 actinomycetes were isolated which were found to belong the 14 different genera of actinomycetes. Mainly the genus Streptomyces was dominant in all the soil samples. Out of 512 isolates recovered, 23.44% exhibited antibacterial activity against one or more tested bacterial pathogens. Of these 56.67% showed activity against Gram-positive bacteria, 26.67% against Gram-negative bacteria while 16.67% showed broad spectrum activity. Isolate DV1S and GR9a-5 showed highest antibacterial properties against several multi-drug resistant bacterial pathogens and were identified using polyphasic approach. DV1S and GR9a-5 were found to be most closely related with S. massasporeus NBRC 12796T and Nocardia nova JCM 6044T respectively. Conclusion The results of this study strongly support the idea that the viable count of actinomycetes varied greatly with altitude. The actinomycetes species isolated from valleys, mid hills and high hills possess significant capacity to produce compounds which are active against several drug resistant bacterial pathogens. PMID:24475340
Kumar, Vijay; Bisht, Gajraj Singh; Gusain, Omprakash
Antibacterial Activity of and Resistance to Small Molecule Inhibitors of the ClpP Peptidase
There is rapidly mounting evidence that intracellular proteases in bacteria are compelling targets for antibacterial drugs. Multiple reports suggest that the human pathogen Mycobacterium tuberculosis and other actinobacteria may be particularly sensitive to small molecules that perturb the activities of self-compartmentalized peptidases, which catalyze intracellular protein turnover as components of ATP-dependent proteolytic machines. Here, we report chemical syntheses and evaluations of structurally diverse ?-lactones, which have a privileged structure for selective, suicide inhibition of the self-compartmentalized ClpP peptidase. ?-lactones with certain substituents on the ?- and ?-carbons were found to be toxic to M. tuberculosis. Using an affinity-labeled analog of a bioactive ?-lactone in a series of chemical proteomic experiments, we selectively captured the ClpP1P2 peptidase from live cultures of two different actinobacteria that are related to M. tuberculosis. Importantly, we found that the growth inhibitory ?-lactones also inactivate the M. tuberculosis ClpP1P2 peptidase in vitro via formation of a covalent adduct at the ClpP2 catalytic serine. Given the potent antibacterial activity of these compounds and their medicinal potential, we sought to identify innate mechanisms of resistance. Using a genome mining strategy, we identified a genetic determinant of ?-lactone resistance in Streptomyces coelicolor, a non-pathogenic relative of M. tuberculosis. Collectively, these findings validate the potential of ClpP inhibition as a strategy in antibacterial drug development and define a mechanism by which bacteria could resist the toxic effects of ClpP inhibitors. PMID:24047344
Compton, Corey L.; Schmitz, Karl R.; Sauer, Robert T.; Sello, Jason K.
Methyl-Hydroxylamine as an Efficacious Antibacterial Agent That Targets the Ribonucleotide Reductase Enzyme
The emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. Ribonucleotide reductase (RNR) is a key enzyme in DNA replication that acts by converting ribonucleotides into the corresponding deoxyribonucleotides, which are the building blocks of DNA replication and repair. RNR has been extensively studied as an ideal target for DNA inhibition, and several drugs that are already available on the market are used for anticancer and antiviral activity. However, the high toxicity of these current drugs to eukaryotic cells does not permit their use as antibacterial agents. Here, we present a radical scavenger compound that inhibited bacterial RNR, and the compound's activity as an antibacterial agent together with its toxicity in eukaryotic cells were evaluated. First, the efficacy of N-methyl-hydroxylamine (M-HA) in inhibiting the growth of different Gram-positive and Gram-negative bacteria was demonstrated, and no effect on eukaryotic cells was observed. M-HA showed remarkable efficacy against Mycobacterium bovis BCG and Pseudomonas aeruginosa. Thus, given the M-HA activity against these two bacteria, our results showed that M-HA has intracellular antimycobacterial activity against BCG-infected macrophages, and it is efficacious in partially disassembling and inhibiting the further formation of P. aeruginosa biofilms. Furthermore, M-HA and ciprofloxacin showed a synergistic effect that caused a massive reduction in a P. aeruginosa biofilm. Overall, our results suggest the vast potential of M-HA as an antibacterial agent, which acts by specifically targeting a bacterial RNR enzyme. PMID:25782003
Julißn, Esther; Baelo, Aida; GavaldÓ, Joan; Torrents, Eduard
What makes a natural clay antibacterial?
Chemical analyses of E. coli killed by aqueous leachates of an antibacterial clay show that intracellular concentrations of Fe and P are elevated relative to controls. Phosphorus uptake by the cells supports a regulatory role of polyphosphate or phospholipids in controlling Fe2+. Fenton reaction products can degrade critical cell components, but we deduce that extracellular processes do not cause cell death. Rather, Fe2+ overwhelms outer membrane regulatory proteins and is oxidized when it enters the cell, precipitating Fe3+ and producing lethal hydroxyl radicals.
Williams, Lynda B.; Metge, David W.; Eberl, Dennis D.; Harvey, Ronald W.; Turner, Amanda G.; Prapaipong, Panjai; Port-Peterson, Amisha T.
Antibacterial endiandric acid derivatives from Beilschmiedia anacardioides.
Three endiandric acid derivatives, beilschmiedic acids A, B and C were isolated from the stem bark of Beilschmiedia anacardioides together with the known beta-sitosterol. Their structures were established by means of modern spectroscopic techniques. The relative configuration of compound 1 was determined by single crystal X-ray analysis. The antibacterial activities of compounds A,B,C were evaluated in vitro against five strains of microbes. Compound C showed strong activity against Bacillus subtilis, Micrococcus luteus and Streptococcus faecalis (MICs below 23 microM). This Compound was more active than the reference antibiotic ampicillin against B. subtilis and M. luteus. PMID:19345383
Chouna, Jean Rodolphe; Nkeng-Efouet, Pepin Alango; Lenta, Bruno Ndjakou; Devkota, Krishna Prasad; Neumann, Beate; Stammler, Hans-Georg; Kimbu, Samuel Fon; Sewald, Norbert
Nanostructured medical sutures with antibacterial properties.
Bacterial repellence in suture materials is a desirable property that can potentially improve the healing process by preventing infection. We describe a method for generating nanostructures at the surface of commercial sutures of different composition, and their potential for preventing biofilm formation. We show how bacteria attachment is altered in the presence of nanosized topographies and identify optimum designs for preventing it without compromising biocompatibility and applicability in terms of nanostructure robustness or tissue friction. These studies open new possibilities for flexible and cost-effective realization of topography-based antibacterial coatings for absorbable biomedical textiles. PMID:25818435
Serrano, Cristina; GarcĒa-Fernßndez, Luis; Fernßndez-Blßzquez, Juan Pedro; Barbeck, Mike; Ghanaati, Shahram; Unger, Ron; Kirkpatrick, James; Arzt, Eduard; Funk, Lutz; Tur¾n, Pau; Del Campo, Arßnzazu
Antibacterial chemoprophylaxis in the prevention of traveler's diarrhea: evaluation of poorly absorbed oral rifaximin.
The use of antibacterial drugs was first shown to effectively reduce the occurrence of traveler's diarrhea nearly 50 years ago. The approach was not encouraged for general use by a Consensus Development Conference in 1985 because of concerns about adverse effects of the drugs and the possible development of resistance against systemically absorbed drugs. When therapy with poorly absorbed rifaximin was shown to be as effective as therapy with systemically absorbed drugs in shortening the duration of traveler's diarrhea, without the development of resistant coliform flora, the use of rifaximin for the prevention of traveler's diarrhea was studied. In the present study, rifaximin provided 72% protection against the development of diarrhea and 77% protection against active or treated diarrhea during 2 weeks of drug administration to United States students in Mexico. Rifaximin offers a potentially useful approach for preventing traveler's diarrhea. Potential areas of future study include use of the drug to prevent diarrhea due to mucosally invasive bacteria, including ciprofloxacin-resistant Campylobacter species, and to reduce the occurrence of postinfectious irritable bowel syndrome. PMID:16267721
DuPont, Herbert L; Jiang, Zhi-Dong; Okhuysen, Pablo C; Ericsson, Charles D; de la Cabada, F Javier; Ke, Shi; DuPont, Margaret W; Martinez-Sandoval, Francisco
In vitro antibacterial and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp
Honokiol and magnolol, two major phenolic constituents of Magnolia sp., have been known to exhibit antibacterial activities. However, until now, their antibacterial activity against Propionibacterium sp. has not been reported. To this end, the antibacterial activities of honokiol and magnolol were detected using the disk diffusion method and a two-fold serial dilution assay. Honokiol and magnolol showed strong antibacterial activities
Junho Park; Jongsung Lee; Eunsun Jung; Yumi Park; Kukhyun Kim; Kwangseon Jung; Jieun Kim
Bactericidal Activities of BMS-284756, a Novel Des-F(6)-Quinolone, against Staphylococcus aureus Strains with Topoisomerase Mutations
The antistaphylococcal activities of BMS-284756 (T-3811ME), levofloxacin, moxifloxacin, and ciprofloxacin were compared against wild-type and grlA and grlA/gyrA mutant strains of Staphylococcus aureus. BMS-284756 was the most active quinolone tested, with MICs and minimal bactericidal concentrations against S. aureus wild-type strain MT5, grlA mutant MT5224c4, and grlA/gyrA mutant EN8 of 0.03 and 0.06, 0.125 and 0.125, and 4 and 4 ?g/ml, respectively. In the time-kill studies, BMS-284756 and levofloxacin exhibited rapid killing against all strains. Ciprofloxacin, however, was not bactericidal for the double mutant, EN8. BMS-284756 and levofloxacin were bactericidal (3 log10 decrease in CFU/ml) against the MT5 and MT5224c4 strains at two and four times the MIC within 2 to 4 h. Against EN8, BMS-284756 was bactericidal within 4 h at two and four times the MIC, and levofloxacin achieved similar results within 4 to 6 h. Both the wild-type strain MT5 and grlA mutant MT5224c4 should be considered susceptible to both BMS-284756 and levofloxacin, and both quinolones are predicted to have clinical efficacy. The in vivo efficacy of BMS-284756, levofloxacin, and moxifloxacin against S. aureus strain ISP794 and its single mutant 2C6(1)-1 directly reflected the in vitro activity: increased MICs correlated with decreased in vivo efficacy. The 50% protective doses of BMS-284756 against wild-type and mutant strains were 2.2 and 1.6 mg/kg of body weight/day, respectively, compared to the levofloxacin values of 16 and 71 mg/kg/day and moxifloxacin values of 4.7 and 61.6 mg/kg/day. BMS-284756 was more potent than levofloxacin and equipotent with moxifloxacin against ISP794 both in vitro and in vivo, while BMS-284756 was more potent than levofloxacin and moxifloxacin against 2C6(1)-1. PMID:11751133
Lawrence, Laura E.; Frosco, MaryBeth; Ryan, Brenda; Chaniewski, Susan; Yang, Hyekyung; Hooper, David C.; Barrett, John F.
Discovery of Antibacterial Biotin Carboxylase Inhibitors by Virtual Screening and Fragment-Based Approaches
As part of our effort to inhibit bacterial fatty acid biosynthesis through the recently validated target biotin carboxylase, we employed a unique combination of two emergent lead discovery strategies. We used both de novo fragment-based drug discovery and virtual screening, which employs 3D shape and electrostatic property similarity searching. We screened a collection of unbiased low-molecular-weight molecules and identified a structurally diverse collection of weak-binding but ligand-efficient fragments as potential building blocks for biotin carboxylase ATP-competitive inhibitors. Through iterative cycles of structure-based drug design relying on successive fragment costructures, we improved the potency of the initial hits by up to 3000-fold while maintaining their ligand-efficiency and desirable physicochemical properties. In one example, hit-expansion efforts resulted in a series of amino-oxazoles with antibacterial activity. These results successfully demonstrate that virtual screening approaches can substantially augment fragment-based screening approaches to identify novel antibacterial agents.
Mochalkin, Igor; Miller, J. Richard; Narasimhan, Lakshmi; Thanabal, Venkataraman; Erdman, Paul; Cox, Philip B.; Prasad, J.V.N. Vara; Lightle, Sandra; Huband, Michael D.; Stover, C. Kendall; Pfizer
Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents.
As a result of increasing drug resistance in pathogenic bacteria, there is a critical need for novel broad-spectrum antibacterial agents. As fatty acid synthesis (FAS) in bacteria is an essential process for cell survival, the enzymes involved in the FAS pathway have emerged as promising targets for antimicrobial agents. Several lines of evidence have indicated that bacterial condensing enzymes are central to the initiation and elongation steps in bacterial fatty acid synthesis and play a pivotal role in the regulation of the entire fatty acid synthesis pathway. beta-ketoacyl-acyl carrier protein (ACP) synthases (KAS) from various bacterial species have been cloned, expressed and purified in large quantities for detailed enzymological, structural and screening studies. Availability of purified KAS from a variety of bacteria, along with a combination of techniques, including combinatorial chemistry, high-throughput screening, and rational drug design based on crystal structures, will undoubtedly aid in the discovery and development of much needed potent and broad-spectrum antibacterial agents. In this review we summarize the biochemical, biophysical and inhibition properties of beta-ketoacyl-ACP synthases from a variety of bacterial species. PMID:12570782
Khandekar, Sanjay S; Daines, Robert A; Lonsdale, John T
Synthesis, cytotoxicity and antibacterial activity of new esters of polyether antibiotic - salinomycin.
A series of 12 novel ester derivatives of naturally occurring polyether antibiotic - salinomycin were synthesized, characterised by spectroscopic method and evaluated for their in vitro antibacterial activity and cytotoxicity. The new esters were demonstrated to form complexes with monovalent and divalent metal cation of 1:1 stoichiometry in contrast to the salinomycin which forms only complexes with monovalent cations. All the obtained compounds show potent antiproliferative activity against human cancer cell lines and a good selectivity index for cancer versus mammalian cells. Additionally, 3 compounds showed higher antiproliferative activity against the drug-resistant cancer cells and lower toxicity towards normal cells than those of unmodified salinomycin and standard anticancer drugs such as cisplatin and doxorubicin. Some of the synthesized compounds showed good inhibitory activity against Staphylococcus strains and clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE). These studies show that salinomycin esters are interesting scaffolds for the development of novel anticancer and Gram-positive antibacterial agents. PMID:24602789
Antoszczak, Micha?; Popiel, Katarzyna; Stefa?ska, Joanna; Wietrzyk, Joanna; Maj, Ewa; Janczak, Jan; Michalska, Greta; Brzezinski, Bogumil; Huczy?ski, Adam
Antibacterial activities of gold and silver nanoparticles against Escherichia coli and bacillus Calmette-Guķrin
Background Diseases such as tuberculosis (TB) have always had a large impact on human health. Bacillus Calmette-Guķrin (BCG) is used as a surrogate for TB during the development of anti-TB drugs. Nanoparticles (NPs) have attracted great interest in drug development. The purpose of this study was to examine the potential of NPs as anti-TB compounds by studying the interacting mechanisms between NPs and bacteria. Results We investigated effects of gold and silver NPs on BCG and Escherichia coli. Experimentally, particle size and shape were characterized using transmission electron microscopy (TEM). Different concentrations of NPs were applied in bacterial culture. The growth of E. coli was monitored through colony forming units (CFU). The mechanism of interaction between NPs and bacteria was analyzed through bacterial thin sections followed by TEM and scanning electron microscopy. Antibacterial effects on BCG were observed by recording fluorescent protein expression levels. Conclusions The results suggest NPs have potential applications as anti-TB compounds. The antibacterial effects and mechanism of action for NPs were dependent upon composition and surface modifications. PMID:22559747
Comparative Analysis of Viperidae Venoms Antibacterial Profile: a Short Communication for Proteomics
Bacterial infections involving multidrug-resistant strains are one of the ten leading causes of death and an important health problem in need for new antibacterial sources and agents. Herein, we tested and compared four snake venoms (Agkistrodon rhodostoma, Bothrops jararaca, B. atrox and Lachesis muta) against 10 Gram-positive and Gram-negative drug-resistant clinical bacteria strains to identify them as new sources of potential antibacterial molecules. Our data revealed that, as efficient as some antibiotics currently on the market (minimal inhibitory concentration (MIC) = 1¢32 ?g mL?1), A. rhodostoma and B. atrox venoms were active against Staphylococcus epidermidis and Enterococcus faecalis (MIC = 4.5 ?g mL?1), while B. jararaca inhibited S. aureus growth (MIC = 13 ?g ml?1). As genomic and proteomic technologies are improving and developing rapidly, our results suggested that A. rhodostoma, B. atrox and B. jararaca venoms and glands are feasible sources for searching antimicrobial prototypes for future design new antibiotics against drug-resistant clinical bacteria. They also point to an additional perspective to fully identify the pharmacological potential of these venoms by using different techniques. PMID:18955360
Ferreira, Bruno L.; Santos, Dilvani O.; dos Santos, Andrķ Luis; Rodrigues, Carlos R.; de Freitas, CĒcero C.; Cabral, L·cio M.; Castro, Helena C.
Discovery of the highly potent fluoroquinolone-based benzothiazolyl-4-thiazolidinone hybrids as antibacterials.
A new series of fluoroquinolone-based benzothiazolyl-4-thiazolidinone hybrids has been yielded via sulfated tungstate-promoted highly accelerated N-formylation at a piperazine residue of ciprofloxacin and norfloxacin entities. The formylated fluoroquinolone moieties were then coupled with substituted 2-aminobenzothiazoles, which were generated from their respective para-substituted amines to form corresponding Schiff base intermediates. The Schiff bases were then treated with thioglycolic acid to equip a new class of 4-thiazolidinones to be analyzed for their antibacterial effects against two Gram-positive (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains and were found highly potent with lowest Minimum inhibitory concentrations (MIC), 1-2 ?g/mL, that is, more potent than control drugs ciprofloxacin (3.12-6.25 ?g/mL). Initial outcomes provided for these novel molecular systems will aid researchers to design and develop new antibacterial drugs. The structural assignments of the new products were done on the basis of FT-IR, (1) H NMR and (13) C NMR spectroscopy, and elemental analysis. PMID:24524270
Patel, Rahul V; Park, Se Won
Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering.
Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad-spectrum antibiotic lead was generated with significantly improved activity, including against all Gram-negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering. PMID:25650563
LeÜnik, UrÜka; Luke×i?, Tadeja; PodgorÜek, Ajda; Horvat, Jaka; Polak, Toma×; Ŗala, Martin; Jenko, Branko; Harmrolfs, Kirsten; Ocampo-Sosa, Alain; MartĒnez-MartĒnez, Luis; Herron, Paul R; Fujs, Ŗtefan; Kosec, Gregor; Hunter, Iain S; M³ller, Rolf; Petkovi?, Hrvoje
Synthesis, characterization, controlled release, and antibacterial studies of a novel streptomycin chitosan magnetic nanoantibiotic
This study describes the preparation, characterization, and controlled release of a streptomycin-chitosan-magnetic nanoparticle-based antibiotic in an effort to improve the treatment of bacterial infections. Specifically, chitosan-magnetic nanoparticles were synthesized by an incorporation method and were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and vibrating sample magnetometry. Streptomycin was incorporated into the nanoparticles to form a streptomycin-coated chitosan-magnetic nanoparticle (Strep-CS-MNP) nanocomposite. The release profiles showed an initially fast release, which became slower as time progressed. The percentage of drug released after 350 minutes was around 100%, and the best fit mathematical model for drug release was the pseudo-second order model. The Strep-CS-MNP nanocomposite showed enhanced antibacterial activity against methicillin-resistant Staphylococcus aureus. This study forms a significant basis for further investigation of the Strep-CS-MNP nanocomposite in the treatment of various bacterial infections. PMID:24549109
Hussein-Al-Ali, Samer Hasan; Zowalaty, Mohamed Ezzat El; Hussein, Mohd Zobir; Ismail, Maznah; Webster, Thomas J
Photodynamic antibacterial effect of graphene quantum dots.
Synthesis of new antibacterial agents is becoming increasingly important in light of the emerging antibiotic resistance. In the present study we report that electrochemically produced graphene quantum dots (GQD), a new class of carbon nanoparticles, generate reactive oxygen species when photoexcited (470Ānm, 1ĀW), and kill two strains of pathogenic bacteria, methicillin-resistant Staphylococcus aureus and Escherichia coli. Bacterial killing was demonstrated by the reduction in number of bacterial colonies in a standard plate count method, the increase in propidium iodide uptake confirming the cell membrane damage, as well as by morphological defects visualized by atomic force microscopy. The induction of oxidative stress in bacteria exposed to photoexcited GQD was confirmed by staining with a redox-sensitive fluorochrome dihydrorhodamine 123. Neither GQD nor light exposure alone were able to cause oxidative stress and reduce the viability of bacteria. Importantly, mouse spleen cells were markedly less sensitive in the same experimental conditions, thus indicating a fairly selective antibacterial photodynamic action of GQD. PMID:24612819
Ristic, Biljana Z; Milenkovic, Marina M; Dakic, Ivana R; Todorovic-Markovic, Biljana M; Milosavljevic, Momir S; Budimir, Milica D; Paunovic, Verica G; Dramicanin, Miroslav D; Markovic, Zoran M; Trajkovic, Vladimir S
Preparation and in vitro antibacterial evaluation of gatifloxacin mucoadhesive gellan system
Background and the purpose of the study The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to precorneal elimination of the drug may be overcome by the use of mucoadhesive in situ gel forming systems that are instilled as drops into the eye and undergo a sol-gel transition in the cul-de-sac and have good mucoadhesion with ocular mucus layers. The objective of this study was to formulate ophthalmic mucoadhesive system of gatifloxacin (GTN) and to evaluate its in vitro antibacterial potential against, Staphylococcus aureus and Escherichia coli. Methods : Mucoadhesive systems were prepared using gellan combined with sodium carboxymethylcellulose (NaCMC) or sodium alginate to enhance the gel bioadhesion properties. The prepared formulations were evaluated for their gelation, and rheological behaviors, mucoadhesion force, in vitro drug release, and antibacterial activity. Results All formulations in non-physiological or physiological conditions showed pseudoplastic behaviors. Increase in the concentration of mucoadhesive agent enhanced the mucoadhesive force significantly. In vitro release of gatifloxacin from the mucoadhesive system in simulated tear fluid (STF, pH of 7.4) was influenced significantly by the properties and concentration of gellan, sodium carboxymethyl cellulose and sodium alginate. Significant reduction in the total bacterial count was observed between drug solution (control) and mucoadhesive batches against both tested organisms. Major conclusion The developed mucoadhesive system is a viable alternative to conventional eye drops of GTN due to its ability to enhance bioavailability through its longer precorneal residence time and ability to sustain the release of the drug. PMID:22615622
Kesavan, K.; Nath, G.; Pandit, JK.
Evaluation of Antibacterial Effectiveness of Desensitizers against Oral Bacteria
Objectives Desensitizers contribute to better clinical results by reducing the rate of cervical dentin sensitivity. However, information on their antibacterial effect is limited. This study examined the antibacterial activities of a triclosan containing (Seal & Protect), a benzalconium containing desensitizer (Micro Prime), a fluoride containing prophilaxy paste (Sultan Desensitizer), two fluoride containing varnishes (Cavity Shealth and Ultra EZ), and a dentin bonding primer (All Bond). Methods The test materials were inserted in the wells of Muller Hinton agar plates inoculated with Streptococcus mutans, Streptococcus salivarious, Staphylococcus aureus, Streptococcus faecalis and Pseudomonas aeruginosa. The diameters of the inhibition zones produced around the materials were measured after 24 h of incubation. The results were analyzed by the Kruskal Wallis one way ANOVA and the Mann-Whitney tests at a significance level of P<.05. Results Micro Prime Desensitizer containing benzalkonium chloride had the highest antibacterial effectiveness compared to other desensitizers used in this study. In addition, triclosan containing Seal & Protect and acidic components containing All Bond showed very high antibacterial efficacy. On the other hand, fluoride within both varnishes had little antibacterial effectiveness. However a fluoride component in a paste (Sultan Desensitizer) showed very high bactericidal effect. Conclusions All desensitizers except fluoride varnishes showed various degrees of antibacterial effect against the bacteria tested in this study. If antibacterial effect is also required from the desensitizersÆ clinicians should avoid use of varnishes. PMID:19212508
Duran, Ismet; Sengun, Abdulkadir; Hadimli, Hasan Huseyin; Ulker, Mustafa
Mechanisms of quinolone resistance in a clinical isolate of Escherichia coli highly resistant to fluoroquinolones but susceptible to nalidixic acid.
Two associated resistance mechanisms were found in a nalidixic acid-susceptible (4 micrograms/ml) but fluoroquinolone-resistant (8 to 16 micrograms/ml) strain of Escherichia coli Q2 selected under norfloxacin therapy. As compared with the susceptible E. coli Q1 isolated before treatment, changes in outer membrane proteins and lipopolysaccharides in Q2 were associated with a 1.5- to 3-fold decrease in the uptake of fluoroquinolones but not nalidixic acid. A 50% inhibition of DNA synthesis in toluene-permeabilized cells of the resistant strain E. coli Q2 required up to 500-fold increased quantities of fluoroquinolones, whereas such inhibition was obtained in both E. coli Q1 and Q2 with similar amounts of nalidixic acid. Selection from E. coli Q1 on norfloxacin of one-step resistant mutants resembling E. coli Q2 was unsuccessful. From these results we infer that a decrease in outer membrane permeability, associated with a peculiar alteration of the DNA gyrase, was responsible for the unusual quinolone resistance phenotype of E. coli Q2. Images PMID:2039202
Moniot-Ville, N; Guibert, J; Moreau, N; Acar, J F; Collatz, E; Gutmann, L
Characterization of plasmid-mediated quinolone resistance determinants in Klebsiella pneumoniae and Escherichia coli from Tokai, Japan.
The spread of plasmid-mediated quinolone resistance (PMQR) determinants was evaluated in 150 ceftazidime or cefotaxime-resistant clinical isolates of Klebsiella pneumoniae and Escherichia coli from Tokai, Japan between 2008 and 2011. In this study, qnrB, qnrS, and aac(6')-Ib-cr genes were detected in 12 (50.0%), 4 (16.7%), and 1 (4.2%) of 24 K. pneumoniae isolates, respectively, while qnrA, aac(6')-Ib-cr, and qepA genes were detected in 1 (0.8%), 11 (8.7%), and 2 (1.6%) of 126 E. coli isolates, respectively. qnr genes were mainly found in K. pneumoniae (66.7%) and to a lesser extent in E. coli (0.8%). We determined the genetic environment of the qnrB4 gene in 24.6 kb class 1 integron structure, including aar-2, cmlA, blaOXA-10, aadA1, qacEdelta1, sul1, and blaDHA-1. In a time-kill assay, introduction of the qnrB4 or qnrS1 plasmid to the recipient E. coli strain decreased the bactericidal activities of fluoroquinolones such as ciprofloxacin, levofloxacin, and pazufloxacin. PMID:25239060
Okade, Hayato; Nakagawa, Satoshi; Sakagami, Toru; Hisada, Harumi; Nomura, Nobuhiko; Mitsuyama, Junichi; Yamagishi, Yuka; Mikamo, Hiroshige
Antibacterials for the prophylaxis and treatment of bacterial endocarditis in children.
Although the overall incidence of infective endocarditis in the paediatric population is considered to be low, over the last 20 years a rising trend in infective endocarditis has been observed among children. This could be due to several reasons including the availability of improved diagnostic techniques, use of continuous central venous catheters and cardiac implants increasing the risk of infection, and the survival of a greater number of infants with congenital heart disease as a result of improved medical management. The predominant causative organisms of paediatric endocarditis include staphylococci and streptococci. There is increased concern surrounding the emergence of endocarditis in children caused by methicillin-resistant Staphylococcus aureus and drug resistant strains of Streptococcus pneumoniae. The treatment approach to paediatric endocarditis is similar to that for adult patients with endocarditis because of similarities in disease pathogenesis and aetiology. The therapeutic goal is to achieve sterilisation of the cardiac vegetations. The choice of antibacterial is dependent upon the susceptibility profile of the causative organism. Vancomycin or gentamicin is recommended for enterococcal endocarditis, according to guidelines from the American Heart Association. For staphylococcal endocarditis in patients with no prosthetic valve, oxacillin or nafcillin with or without gentamicin is the treatment of choice. In the case of endocarditis caused by methicillin-resistant S. aureus, vancomycin is commonly used in patients with no prosthetic valve and a combination of vancomycin, gentamicin and rifampicin (rifampin) for patients with prosthetic material. Cefazolin or ceftriaxone is the treatment of choice for penicillin allergic paediatric patients with endocarditis caused by viridans streptococci. While there have been no major changes in endocarditis therapy for the last decade, the current focus is on the recognition of multiple-drug resistant pathogens and the use of newer agents such as quinupristin/dalfopristin in the treatment of resistant bacterial endocarditis. Prophylactic antibacterial therapy is recommended for procedures thought to be associated with the occurrence of bacteraemia involving organisms commonly associated with endocarditis. These include dental extractions and oral, respiratory tract, genitourinary, gastrointestinal or oesophageal procedures. Prophylactic antibacterials recommended by the American Heart Association during genitourinary and gastrointestinal surgical procedures in high risk patients include ampicillin + gentamicin or vancomycin + gentamicin in high risk patients with penicillin allergy. Ampicillin has been recommended for prophylaxis of bacterial endocarditis in children undergoing oral, respiratory tract or oesophageal procedures. In the case of penicillin allergy in these patients, cephalosporins, clindamycin, azithromycin or clarithromycin have been recommended. The general consensus is that antibacterial prophylaxis during dental procedure is unnecessary, and in fact propagates bacterial resistance. PMID:11706922
Capitano, B; Quintiliani, R; Nightingale, C H; Nicolau, D P
Synthesis and antibacterial activities of antibacterial peptides with a spiropyran fluorescence probe.
In this report, antibacterial peptides 1-3 were prepared with a spiropyran fluorescence probe. The probe exhibits a change in fluorescence when isomerized from a colorless spiro-form (spiropyran, Sp) to a colored open-form (merocyanine, Mc) under different chemical environments, which can be used to study the mechanism of antimicrobial activity. Peptides 1-3 exhibit a marked decrease in antimicrobial activity with increasing alkyl chain length. This is likely due to the Sp-Mc isomers in different polar environments forming different aggregate sizes in TBS, as demonstrated by time-dependent dynamic light scattering (DLS). Moreover, peptides 1-3 exhibited low cytotoxicity and hemolytic activity. These probe-modified peptides may provide a novel approach to study the effect of structural changes on antibacterial activity, thus facilitating the design of new antimicrobial agents to combat bacterial infection. PMID:25358905
Chen, Lei; Zhu, Yu; Yang, Danling; Zou, Rongfeng; Wu, Junchen; Tian, He
Synthesis and Antibacterial Activities of Antibacterial Peptides with a Spiropyran Fluorescence Probe
In this report, antibacterial peptides1-3 were prepared with a spiropyran fluorescence probe. The probe exhibits a change in fluorescence when isomerized from a colorless spiro-form (spiropyran, Sp) to a colored open-form (merocyanine, Mc) under different chemical environments, which can be used to study the mechanism of antimicrobial activity. Peptides 1-3 exhibit a marked decrease in antimicrobial activity with increasing alkyl chain length. This is likely due to the Sp-Mc isomers in different polar environments forming different aggregate sizes in TBS, as demonstrated by time-dependent dynamic light scattering (DLS). Moreover, peptides 1-3 exhibited low cytotoxicity and hemolytic activity. These probe-modified peptides may provide a novel approach to study the effect of structural changes on antibacterial activity, thus facilitating the design of new antimicrobial agents to combat bacterial infection. PMID:25358905
Chen, Lei; Zhu, Yu; Yang, Danling; Zou, Rongfeng; Wu, Junchen; Tian, He
... of club drugs include Gamma hydroxybutyrate (GHB), Rohypnol, ketamine, as well as MDMA (ecstasy) and methamphetamine ( Drug ... Club Drugs , National Institute on Drug Abuse, 2010). Ketamine is a dissociative anesthetic, mostly used in veterinary ...
Molecular Basis for the Differential Quinolone Susceptibility of Mycobacterial DNA Gyrase
DNA gyrase is a type II topoisomerase that catalyzes the introduction of negative supercoils in the genomes of eubacteria. Fluoroquinolones (FQs), successful as drugs clinically, target the enzyme to trap the gyrase-DNA complex, leading to the accumulation of double-strand breaks in the genome. Mycobacteria are less susceptible to commonly used FQs. However, an 8-methoxy-substituted FQ, moxifloxacin (MFX), is a potent antimycobacterial, and a higher susceptibility of mycobacterial gyrase to MFX has been demonstrated. Although several models explain the mechanism of FQ action and gyrase-DNA-FQ interaction, the basis for the differential susceptibility of mycobacterial gyrase to various FQs is not understood. We have addressed the basis of the differential susceptibility of the gyrase and revisited the mode of action of FQs. We demonstrate that FQs bind both Escherichia coli and Mycobacterium tuberculosis gyrases in the absence of DNA and that the addition of DNA enhances the drug binding. The FQs bind primarily to the GyrA subunit of mycobacterial gyrase, while in E. coli holoenzyme is the target. The binding of MFX to GyrA of M. tuberculosis correlates with its effectiveness as a better inhibitor of the enzyme and its efficacy in cell killing. PMID:24419347
Kumar, Rupesh; Madhumathi, Bhavani Shankar
Evaluation of antibacterial and anthelmintic activities with total phenolic contents of Piper betel leaves
Objective: The study was conducted to investigate the antibacterial and anthelmintic activities and to determine total phenolic contents of methanolic extract of Piper betel leaves. Materials and Methods: The extract was subjected to assay for antibacterial activity using both gram positive and gram negative bacterial strains through disc diffusion method; anthelmintic activity with the determination of paralysis and death time using earthworm (Pheritima posthuma) at five different concentrations and the determination of total phenolic contents using the Folin-ciocalteau method. Results: The extract showed significant (p<0.01) zone of inhibitions against gram positive Staphylococcus aureus [(6.77▒0.25) mm] and Gram negative Escherichia coli [(8.53▒0.25) mm], Salmonella typhi [(5.20▒0.26) mm], Shigella dysenteriae [(11.20▒0.26) mm] compared to positive control Azithromycin (ranging from 20.10▒0.17 to 25.20▒0.35 mm) while no zone inhibitory activity was found for both the extract and the standard drug against Gram positive Bacillus cereus. The extract also showed potent anthelmintic activity requiring less time for paralysis and death compared to the standard drug albendazole (10 mg/ml). At concentrations 10, 20, 40, 60 and 80 mg/ml, leaves extract showed paralysis at mean time of 9.83▒0.60, 8.50▒0.29, 6.60▒0.17, 6.20▒0.44 and 4.16▒0.60; death at 11.33▒0.88, 9.67▒0.33, 7.83▒0.17, 7.16▒0.60 and 5.16▒0.72 minutes, respectively. Whereas the standard drug showed paralysis and death at 19.33▒0.71 and 51.00▒0.23 minutes respectively. The extract confirmed the higher concentration of phenolic contents (124.42▒0.14 mg of GAE /g of extract) when screened for total phenolic compounds. Conclusion: As results confirmed potential antibacterial and anthelmintic activities of Piper betel leaves extract, therefore it may be processed for further drug research. PMID:25386394
Akter, Kazi Nahid; Karmakar, Palash; Das, Abhijit; Anonna, Shamima Nasrin; Shoma, Sharmin Akter; Sattar, Mohammad Mafruhi
Cobra Cytotoxins: Structural Organization and Antibacterial Activity
Cardiotoxins (cytotoxins, CT) are ?-structured proteins isolated from the venom of cobra. They consist of 59¢61 amino acid residues, whose antiparallel chains form three æfingersÆ. In contrast to neurotoxins with an overall similar fold, CTs are amphiphilic. The amphiphilicity is caused by positively charged lysine and arginine residues flanking the tips of the loops that consist primarily of hydrophobic amino acids. A similar distribution of amino acid residues is typical for linear (without disulfide bonds) cationic cytolytic peptides from the venoms of other snakes and insects. Many of them are now considered to be lead compounds in combatting bacterial infections and cancer. In the present review, we summarize the data on the antibacterial activity of CTs and compare it to the activity of linear peptides. PMID:25349711
Dubovskii, P. V.; Utkin, Y. N.
Antibacterial Mechanisms of Polymyxin and Bacterial Resistance
Multidrug resistance in pathogens is an increasingly significant threat for human health. Indeed, some strains are resistant to almost all currently available antibiotics, leaving very limited choices for antimicrobial clinical therapy. In many such cases, polymyxins are the last option available, although their use increases the risk of developing resistant strains. This review mainly aims to discuss advances in unraveling the mechanisms of antibacterial activity of polymyxins and bacterial tolerance together with the description of polymyxin structure, synthesis, and structural modification. These are expected to help researchers not only develop a series of new polymyxin derivatives necessary for future medical care, but also optimize the clinical use of polymyxins with minimal resistance development. PMID:25664322
Qin, Wangrong; Fang, Shisong; Qiu, Juanping
Antibacterial properties of composite UHMWPE/ surfaces
NASA Astrophysics Data System (ADS)
Due to the diffusion of severe pathogens, everyday life is exposed to the risks of contracting severe diseases. For this reason, efficient antimicrobial surfaces are of paramount importance. In this work we present the first evidences of a new technique to obtain an antibacterial ultra high molecular weight polyethylene based on a non-stoichiometric, visible light responsive, titanium oxide coating. The coating was obtained through a process in which titanium ions, resulting from laser ablation of a corresponding target, were accelerated and implanted on the samples. The samples were tested against a Staphylococcus aureus strain, in order to assay their antimicrobial efficacy. Results show that this treatment strongly discourages bacterial colonization of the treated surfaces.
Delle Side, D.; Nassisi, V.; Giuffreda, E.; Velardi, L.; Alifano, P.; TalÓ, A.; Tredici, S. M.
Phytochemical constituents and antibacterial activity of some green leafy vegetables
Objective To investigate the antibacterial activity and photochemicals of five green leafy vegetables against a panel of five bacteria strains. Methods Disc diffusion method was used to determine the antibacterial activity, while kanamycin was used as a reference antibiotic. The phytochemical screening of the extracts was performed using standard methods. Results All methanol extracts were found active against all the test bacterial strains. Overall maximum extracts shows antibacterial activity which range from 6 to 15 mm. Proteins and carbohydrates was found in all the green leaves, whereas alkaloid, steroids, saponins, flavonoids, tannins were found in most of the test samples. Conclusions The obtain result suggests that green leafy vegetables have moderate antibacterial activity and contain various pharmacologically active compounds and thus provide the scientific basis for the traditional uses of the studied vegetables in the treatment of bacterial infections. PMID:25182436
Bhat, Ramesa Shafi; Al-Daihan, Sooad
Antibacterial activity in the hemolymph of myriapods (Arthropoda).
The hemolymphs of two diplopod (Chicobolus sp. and Rhapidostreptus virgator) and two chilopod species (Lithobius forficatus and Scolopendra cingulata) were tested for the presence of antibacterial substances using Petri dish tests. The native hemolymph of all species had substances acting on living Micrococcus luteus, whereas only Rhapidostreptus, Scolopendra, and Lithobius were effective against lyophilized Micrococcus. The antibacterial activity against living Micrococcus increased after inoculation with bacteria (Enterobacter cloacae beta-12) in Chicobolus and Rhapidostreptus and also against lyophilized Micrococcus in the latter. Thus, these effects appear to be inducible. None of the myriapods tested had any bacteriostatic effect on Escherichia coli D-31 whereas the growth of gram-negative E. cloacae was inhibited. The antibacterial substances in the diplopod species were unstable when heated but were resistant to freezing. At least two antibacterial substances (a lysozyme-like one and another substance) are considered to occur in Myriapoda. PMID:2273286
Xylander, W E; Nevermann, L
Pharmacology of novel heteroaromatic polycycle antibacterials.
Heteroaromatic polycycle (HARP) compounds are a novel class of small (M(w), 600 to 650) DNA-binding antibacterials. HARP compounds exhibit a novel mechanism of action by preferentially binding to AT-rich sites commonly found in bacterial promoters and replication origins. Noncovalent binding in the minor groove of DNA results in inhibition of DNA replication and DNA-dependent RNA transcription and subsequent bacterial growth. HARP compounds have previously been shown to have potent in vitro activities against a broad spectrum of gram-positive organisms. The present report describes the extensive profiling of the in vitro and in vivo pharmacology of HARP antibacterials. The efficacies of representative compounds (GSQ-2287, GSQ-10547, and GSQ-11203), which exhibited good MIC activity, were tested in murine lethal peritonitis and neutropenic thigh infection models following intravenous (i.v.) administration. All compounds were efficacious in vivo, with potencies generally correlating with MICs. GSQ-10547 was the most potent compound in vitro and in vivo, with a 50% effective dose in the murine lethal peritonitis model of 7 mg/kg of body weight against methicillin-sensitive Staphylococcus aureus (MSSA) and 13 mg/kg against methicillin-resistant S. aureus (MRSA). In the neutropenic mouse thigh infection model, GSQ-11203 reduced the bacterial load (MRSA and MSSA) 2 log units following administration of a 25-mg/kg i.v. dose. In a murine lung infection model, treatment with GSQ-10547 at a dose of 50 mg/kg resulted in 100% survival. In addition to determination of efficacy in animals, the pharmacokinetic and tissue disposition profiles in animals following administration of an i.v. dose were determined. The compounds were advanced into broad safety screening studies, including screening for safety pharmacology, genotoxicity, and rodent toxicity. The results support further development of this novel class of antibiotics. PMID:14576101
Gross, M; B³rli, R; Jones, P; Garcia, M; Batiste, B; Kaizerman, J; Moser, H; Jiang, V; Hoch, U; Duan, J-X; Tanaka, R; Johnson, K W
Pharmacology of Novel Heteroaromatic Polycycle Antibacterials
Heteroaromatic polycycle (HARP) compounds are a novel class of small (Mw, 600 to 650) DNA-binding antibacterials. HARP compounds exhibit a novel mechanism of action by preferentially binding to AT-rich sites commonly found in bacterial promoters and replication origins. Noncovalent binding in the minor groove of DNA results in inhibition of DNA replication and DNA-dependent RNA transcription and subsequent bacterial growth. HARP compounds have previously been shown to have potent in vitro activities against a broad spectrum of gram-positive organisms. The present report describes the extensive profiling of the in vitro and in vivo pharmacology of HARP antibacterials. The efficacies of representative compounds (GSQ-2287, GSQ-10547, and GSQ-11203), which exhibited good MIC activity, were tested in murine lethal peritonitis and neutropenic thigh infection models following intravenous (i.v.) administration. All compounds were efficacious in vivo, with potencies generally correlating with MICs. GSQ-10547 was the most potent compound in vitro and in vivo, with a 50% effective dose in the murine lethal peritonitis model of 7 mg/kg of body weight against methicillin-sensitive Staphylococcus aureus (MSSA) and 13 mg/kg against methicillin-resistant S. aureus (MRSA). In the neutropenic mouse thigh infection model, GSQ-11203 reduced the bacterial load (MRSA and MSSA) 2 log units following administration of a 25-mg/kg i.v. dose. In a murine lung infection model, treatment with GSQ-10547 at a dose of 50 mg/kg resulted in 100% survival. In addition to determination of efficacy in animals, the pharmacokinetic and tissue disposition profiles in animals following administration of an i.v. dose were determined. The compounds were advanced into broad safety screening studies, including screening for safety pharmacology, genotoxicity, and rodent toxicity. The results support further development of this novel class of antibiotics. PMID:14576101
Gross, M.; B³rli, R.; Jones, P.; Garcia, M.; Batiste, B.; Kaizerman, J.; Moser, H.; Jiang, V.; Hoch, U.; Duan, J.-X.; Tanaka, R.; Johnson, K. W.