A method of treating a biofilm on a surface, comprising: providing a surface having a biofilm; and administering to the surface a treatment that reduces a concentration of pyruvate of the biofilm, comprising pyruvate produced by at least a portion the biofilm, under conditions effective reducing maintenance of the biofilm on the surface. A composition, comprising purified enzyme, within a particle, effective for reducing pyruvate concentration in an aqueous suspension of the composition.

Each reference cited herein is expressly incorporated herein in its entirety. Biofilms are surface-associated bacterial communities that are matrix-encased, and may cause persistent and chronic infections in medical settings. Biofilm-related infections include chronic urinary tract infection due to catheters, chronic wounds (e.g., diabetic, burn, surgical), ventilated-associated pneumonia in intubated patients, chronic pulmonary disease in patients with cystic fibrosis or chronic obstructive lung disease. According to the National Institutes of Health, 65 percent of all hospital-acquired infections are due to bacteria growing as biofilms, and 80 percent of chronic infections are linked to biofilms. To put this in perspective, the Center for Disease Control estimates that hospital-acquired infections account for an estimated 1.7 million infections and 99,000 associated deaths each year in American hospitals alone. The high morbidity and mortality rate is due to biofilms being extremely difficult to control in medical settings. In fact, conventional therapies have proven inadequate in the treatment of many (if not most) chronic biofilm infections, due to the extraordinary tolerance of biofilms to available antimicrobial agents relative to their planktonic counterparts, and their ability to inhibit healing.
A hallmark of biofilms is their extreme tolerance to antimicrobial agents, rendering infections by biofilms recalcitrant to conventional treatment therapies. This has brought on the realization that successful treatment of biofilm infections will require the development of novel treatment strategies. It is thus not surprising that biofilm dispersion, a regulatory response to environmental cues, allowing bacterial cells to convert to the planktonic state, has become a major focus of recent research endeavors to combat biofilms. However, while much attention has been paid to agents inducing biofilm dispersion, little is known about the mechanism underlying dispersion. P. aeruginosa has been previously shown to require autogenously produced pyruvate and pyruvate fermentative processes as a means of redox balancing to form microcolonies, with depletion of pyruvate or inactivation of components of the pyruvate fermentation pathway impairing biofilm formation (See FIG. 1). Olga E. Petrova, Jill R. Schurr, Michael J. Schurr, and Karin Sauer, Microcolony formation by the opportunistic pathogen Pseudomonas aeruginosa requires pyruvate and pyruvate fermentation, Molecular Microbiology (2012) 86(4), 819-835, doi:10.1111/mmi.12018.
Bacterial infections are common complication of burn wounds, with surface-associated communities of bacteria known as biofilms forming within human burn wounds within 10-24 hr. of thermal injury. The presence of biofilms in burns is problematic as biofilms are recalcitrant to killing by antimicrobial agents, thus rendering conventional treatment strategies ineffective, with 75% of extensively burned patients dying as a consequence of severe infection.
Cells associated with biofilms are up to 1000-fold less susceptible to various antibiotics than their planktonic counterparts. For instance, the development of antimicrobial burn creams was considered a major advance in the care of burn wound patients, yet infections of wounds remain the most common cause of morbidity and mortality among the 6.5 million people suffering from wounds in the United States alone, causing over 200,000 deaths annually. The most affected are people suffering from burn wounds, for which almost 61% of deaths are caused by infection. Treatment failure has been primarily attributed to the virulence factors produced by the principal wound pathogens Staphylococcus aureus and Pseudomonas aeruginosa as well as their ability to form biofilms in wounds, which are recalcitrant to antibiotic treatment and the host immune defense.
Pseudomonas aeruginosa is responsible for a wide array of persistent infections including those of non-healing wounds and the lungs of cystic fibrosis sufferers. Within the cystic fibrosis lung, P. aeruginosa forms biofilms, defined as complex surface-attached communities encased in an extracellular matrix composed of exopolysaccharides, DNA and proteins. A hallmark of P. aeruginosa biofilms is the presence of complex multicellular aggregates or microcolonies, the formation of which has been observed both in vitro and in vivo (Lam et al., 1980; Høiby et al., 2001; Sauer et al., 2002; Davey et al., 2003; Garcia-Medina et al., 2005; Sriramulu et al., 2005) and has been associated with DNA release and elevated mutation rates (Allesen-Holm et al., 2006; Conibear et al., 2009). Iron has been demonstrated to control microcolony formation, as P. aeruginosa mutants inactivated in the high-affinity pyoverdine iron acquisition system only form thin unstructured biofilms even when grown in iron-sufficient medium (Banin et al., 2005). While the findings implicated iron as a signal for development of mushroom-like microcolonies, Yang et al. (2007) demonstrated microcolony formation to be favored in media with low iron availability, with increasing iron concentrations resulting in decreased microcolony formation and DNA release. Microcolony formation coincides with the formation of steep oxygen and nutrient gradients, with cells located deep within biofilm structures experiencing stressful, growth-limiting conditions (Anderl et al., 2003; Walters et al., 2003; Borriello et al., 2004). Microelectrode analyses have revealed that, while the concentration of oxygen at the surface of the biofilm is similar to that of the bulk fluid, oxygen levels drop rapidly towards the interior of biofilms with the center of microcolonies being essentially anaerobic (de Beer et al., 1994; Stoodley et al., 1994; 1997; Rasmussen and Lewandowski, 1998; Rani et al., 2007). Additional gradients exist in the biofilm environment with respect to microbial waste products, sulphide and hydrogen ions (pH), which may accumulate within the depths of the biofilm (de Beer et al., 1994; Stoodley et al., 1994; 1997; Rasmussen and Lewandowski, 1998; Raniet al., 2007).
The resident bacterial population has been demonstrated to adjust to these steep gradients through various approaches including the modulation of metabolic rates, dormancy, stress responses and mutation rates (Stewart, 1996; Anderl et al., 2000; Walters et al., 2003; Borriello et al., 2004; Lenz et al., 2008; Perez-Osorio et al., 2010). Selected metabolic pathways have been associated with biofilm formation, serving both as contributing factors and adaptations to the changing biofilm microenvironment. For instance, availability of amino acids appears to contribute to biofilm formation, as inactivation of the stationary phase sigma factor RpoS has been shown to enhance biofilm formation by alleviating potential amino acid limitation (Shirtliff et al., 2002). Inactivation of the catabolite repression control (Crc) protein, involved in carbon metabolism regulation and control of type IV pili gene expression, resulted in the formation of cellular monolayers devoid of microcolonies typically observed during normal biofilm development (O'Toole et al., 2000). Furthermore, under conditions of oxygen absence or limitation, P. aeruginosa is able to respire nitrate or nitrite through the process of denitrification, which sequentially reduces nitrate to nitrogen gas through the action of four reductases (Carlson et al., 1982; Carlson and Ingraham, 1983; Davies et al., 1989). The activation/upregulation of the components of the denitrification pathway has been repeatedly observed within in vitro biofilms and during persistent P. aeruginosa infections, with sensing and processing of nitrate and other intermediate forms playing an essential role in the establishment, maintenance, resistance and dispersal of biofilms in vitro and in vivo (Hassett et al., 2002; 2009; Borriello et al., 2004; Barraud et al., 2006; Filiatrault et al., 2006; Alvarez-Ortega and Harwood, 2007; Toyofuku et al., 2007; Van Alst et al., 2007; Schobert and Jahn, 2010). Many environments, however, do not have sufficient nitrate present to drive nitrate respiration. Under conditions of oxygen limitation in the absence of nitrate, growth is driven by oxygen respiration, done using high-affinity terminal oxidases including cbb3-1 and cbb3-2 (Comolli and Donohue, 2004; Alvarez-Ortega and Harwood, 2007).
UspK has been previously shown to be essential for survival on pyruvate under conditions of oxygen limitation (Schreiber et al., 2006), with P. aeruginosa PA14 being able to release pyruvate, using a pyocyanin-dependent mechanism, and subsequently utilize pyruvate during stationary phase (Price-Whelan et al., 2007). Genes associated with pyruvate fermentation are downregulated in mifR mutant biofilms (Tables 3 and S4), pyruvate utilization contributes to biofilm formation and the establishment of microcolonies. Exogenously added pyruvate supports biofilm development in wild type PA14 biofilms. Addition of pyruvate (0.1-1 mM) to the growth medium (diluted LB medium) resulted in enhanced microcolony formation by wild type biofilms with the average diameter of microcolonies increasing 1.6-fold in the presence of 1 mM pyruvate. Addition of 1 mM pyruvate did not enhance growth of P. aeruginosa grown planktonically under fully aerated conditions. However, the presence of 25 mM pyruvate as the sole carbon source supported some growth by P. aeruginosa.
As increased availability of pyruvate coincided with enhanced microcolony formation, when grown in LB or VBMM medium, lack of pyruvate abrogates microcolony formation by enzymatically depleting pyruvate from the growth medium using pyruvate dehydrogenase (PDH). Under the conditions tested, the presence of pyruvate dehydrogenase and the appropriate cofactors (CoA, NADH) did not affect growth in broth when grown in microtiter plates, as determined by absorbance (not shown). However, presence of PDH during the early stages of biofilm development impaired microcolony formation, with PDH-treated biofilms containing infrequent thin and unstructured clusters not exceeding 20 μm in diameter. In contrast, biofilms treated with heat-inactivated PDH or cofactors alone were similar to untreated biofilms and characterized by widespread microcolonies exceeding 150 μm in diameter.
The findings strongly supported a requirement for pyruvate in the process of biofilm microcolony formation regardless of medium used.
NADH-dependent lactate dehydrogenase LdhA has been previously shown to be required for anaerobic pyruvate utilization and long-time survival on pyruvate (Eschbach et al., 2004). In addition, aconitate hydratase AcnA, plays a role in tricarboxylic acid cycle, glyoxylate bypass and acetyl-CoA assimilation (and only indirectly in pyruvate utilization) (Somerville et al., 1999; Winsor et al., 2009). Inactivation of acnA resulted in impaired biofilm formation as indicated by biofilms being characterized by up to 10-fold reduced biofilm biomass and thickness as compared to wild type biofilms. Complementation restored biofilm formation to wild type levels. Similarly, expression of mifR in the acnA mutant did result in significantly enhanced biofilm and microcolony formation, with parameters including biomass and thickness increasing more than fourfold when compared to the acnA mutant alone. These suggest that, while AcnA contributes to biofilm formation, AcnA acts downstream of MifR and is probably not the direct cause of the MifR or pyruvate-dependent microcolony formation phenotypes. This is in part based on the finding of AcnA being required not only for pyruvate utilization but also for the tricarboxylic acid cycle, glyoxylate bypass and acetyl-CoA assimilation.
Inactivation of ldhA resulted in fourfold reduced biofilm biomass accumulation and reduced thickness while complementation restored biofilm formation to wild type levels. Overall, the architecture of ldhA mutant biofilms was similar to that observed for mifR mutant biofilms and was only composed of small clusters less than 20 μm in diameter. Furthermore, in contrast to the results observed for acnA::Mar, expression of mifR in ldhA mutant biofilms failed to restore biofilm and microcolony formation to wild type levels, with ldhA::Mar/pMJT-mifR demonstrating the same biofilm architecture as the ldhA mutant. This supports a role for LdhA and pyruvate fermentation in microcolony formation.
Exogenous pyruvate and lactate dehydrogenase, associated with pyruvate utilization under limited-oxygen conditions, are required for microcolony formation. The ldhA mutant did not respond to the addition of pyruvate (grown in diluted LB), with the strain demonstrating similar defects in biofilm formation in the absence and presence of exogenous pyruvate. Similar results were obtained when VBMM medium was used. Expression of ldhA in PA14, while not increasing the overall biofilm biomass, correlated with a significant increase in microcolony formation. The increase in microcolony formation was comparable to the increase observed upon pyruvate addition. Expression of ldhA in mifR mutant biofilms fully restored the biofilm architecture to wild type levels, resulting in a significant increase in biofilm biomass accumulation and more importantly, the formation of microcolonies exceeding >150 μm in diameter. To determine whether ldhA mutant biofilms demonstrated a significantly increased NADH/NAD+ratio compared to wild type, while overexpression of ldhA significantly decreased the available NADH as indicated by a decreased NADH/NAD+ratio compared to wild type biofilms. There is thus an inverse correlation between NADH/NAD+ratio and microcolony formation. The presence of pyocyanin has been demonstrated to alter NADH/NAD+ratios (Price-Whelan et al., 2007).
Differential expression of ldhA resulted in an overall similar trend with respect to NADH/NAD+ratios as those obtained under biofilm growth conditions, with ldhA mutant demonstrating increased NADH/NAD+ratios and overexpression of ldhA correlating with decreased NADH/NAD+ratios compared to wild type. Inactivation of mifR resulted in significantly increased NADH/NAD+ratio compared to wild type, while expression of mifR or ldhA in mifR mutants restored the NADH/NAD+ratio to wild type levels. There is thus a requirement for pyruvate in biofilm microcolony formation, with the observed effects likely being mediated via the pyruvate fermentation pathway, probably as a means of redox balancing.
P. aeruginosa is capable of fermentatively utilizing pyruvate for survival under conditions of oxygen limitation in the absence of nitrite and nitrate (Eschbach et al., 2004; Schreiber et al., 2006). The process involves the conversion of pyruvate to lactate, acetate and/or succinate, with the lactate and acetate-producing branches of the pathway apparently predominating. Inactivation of lactate dehydrogenase (LdhA), which converts pyruvate to lactate and regenerates NAD+, severely impairs pyruvate fermentation and compromises survival on pyruvate under conditions of energy (electron) richness (Eschbach et al., 2004). Pyruvate does not support growth under strictly anaerobic growth conditions. Moreover, while addition of 0.1-1 mM of pyruvate to 24-well grown P. aeruginosa is not sufficient to increase growth, higher concentrations of pyruvate are capable of sustaining growth under aerobic and oxygen limiting (but not anaerobic) conditions. Pyruvate therefore appears to be used as a means of redox balancing. Consistent with a role of LdhA in regenerating reducing equivalents under oxygen-limiting conditions, expression of LdhA in P. aeruginosa wild type correlated with a significant increase in biofilm biomass accumulation and microcolony formation as well as restoration of the mifR mutant biofilm phenotype to wild type levels and decreased NADH/NAD+ratios. Redox balancing appears required to enable microcolony formation in biofilms.
Pyruvate appears to be produced by the resident biofilm bacteria. A model recently proposed by Schobert and Jahn (2010) places P. aeruginosa biofilm cells within different niches, with metabolically active cells exposed to oxygen secreting pyruvate, which then diffuses into the anoxic zones to be utilized by cells residing within these layers. Consistent with this model is the pyruvate-dependent formation of microcolonies, with depletion of extracellular pyruvate impairing biofilm development and abrogating microcolony formation, while addition of exogenous pyruvate enhances biofilm development by specifically promoting microcolony formation. Pyruvate is released into the extracellular environment by P. aeruginosa PA14 during stationary phase in a manner dependent on the redox-active phenazine pyocyanin (Price-Whelan et al., 2007). Although phenazine production does not impact the ability of P. aeruginosa PA14 to attach to surfaces, mutants unable to synthesize phenazines including pyocyanin were impaired in microcolony formation (Dietrich et al., 2008; Ramos et al., 2010). Moreover, P. aeruginosa PA14 differs from PAO1 with respect to pyocyanin levels with PA14 producing more pyocyanin than PAO1 (Dietrich et al., 2006) as well as secreting more pyruvate (Price-Whelan et al., 2007). Increased pyocyanin and pyruvate release correlates with observation of P. aeruginosa PA14 biofilms forming significantly larger microcolonies following 6 days of growth under continuous flowing conditions and earlier initiation of microcolony formation compared to PAO1.
Usp proteins, which are conserved across all domains of life, have been implicated in the response to hypoxic conditions and establishment of chronic, persistent infections by Mycobacterium tuberculosis (Drumm et al., 2009), stress-mediated adhesion and motility in Escherichia coli (Nachin et al., 2005) and the process of biofilm formation by Porhyromonas gingivalis (Kuramitsu et al., 2005; Chen et al., 2006). In P. aeruginosa, increased expression of all five Usp proteins has been consistently observed under conditions of oxygen limitation, in laboratory-grown biofilms (Yoon et al., 2002; Waite et al., 2006; Alvarez-Ortega and Harwood, 2007), and in the context of in vivo infections (Mashburn et al., 2005; Bielecki et al., 2011). Usp proteins enable anaerobic growth and/or survival of P. aeruginosa, with inactivation of uspN and uspK having been linked to premature cell death during long-term anaerobic existence (Eschbach et al., 2004; Boes et al., 2006; Schreiber et al., 2006). However, UspN and UspK do so via distinct rather than converging mechanisms. UspN is required for survival when cells experience anaerobic energy stress and starvation, with a mutant strain demonstrating significantly reduced cell recovery after prolonged exposure to such conditions (Boes et al., 2006; 2008), while UspK is essential for P. aeruginosa anaerobic survival via pyruvate fermentation (Eschbach et al., 2004; Schreiber et al., 2006). This difference in mechanisms was apparent with respect to microcolony formation. The small biomass accumulation defect observed following UspN inactivation suggests that subpopulations of biofilm cells experiencing anaerobic energy starvation likely utilize systems such as UspN to promote survival. In contrast, inactivation of UspK resulted in severely reduced microcolonies and biomass, strongly supporting a requirement for UspK in microcolony formation. Given that UspK plays a substantial role during fermentative growth on pyruvate, but is not required for denitrification (Schreiber et al., 2006), these findings strongly underscore the requirement for pyruvate fermentation as a means of addressing oxygen limitation of the biofilm microcolony microenvironment and the need for redox balancing.
Bacteria present within microcolonies experience an environment that is distinct from environmental conditions elsewhere in the biofilm. Within microcolonies, P. aeruginosa cells experience low oxygen but energy (electron)-rich conditions and use fermentative processes for survival and growth. In particular, pyruvate is required for microcolony formation by P. aeruginosa with changes in extracellular pyruvate levels positively correlating with average biofilm cellular aggregate sizes. Pyruvate contributes to growth of biofilm microcolonies via pyruvate fermentation as a means of redox balancing with inactivation of lactate dehydrogenase preventing biofilm development and microcolony formation.
Pyruvate dehydrogenase is the enzyme that catalyzes conversion of pyruvate to acetyl-CoA and NADH, with an intermediate decarboxylation, in the presence of CoA and NAD+. Thiamine phosphate (TPP) is required for pyruvate dehydrogenase activity, but TPP is not involved in the biochemical reaction. See FIG. 18, which represents various standard biochemical pathways involving pyruvate.
P. aeruginosa produces and secretes up to 10 mM pyruvate, with pyruvate having been shown to be required for long-term bacterial survival (without serving as a carbon source).
Pyruvate plays an essential role in the formation of biofilms, as continuous depletion of pyruvate (via pyruvate dehydrogenase [PDH, 0.57 U/mg specific activity] plus cofactors) from the growth medium prevented biofilm formation. Pyruvate is required to cope with stressful, oxygen-limiting but electron-rich conditions, referred to as 'reductive stress' (too much NADH/electrons, not enough O2) present in biofilms. This is apparent by the activation of pyruvate fermentation pathways in biofilms, and mutant strains inactivated in genes involved in pyruvate fermentation, including acnA and ldhA encoding aconitase and lactate dehydrogenase, respectively, being unable to form biofilms.
Dispersion is a regulated process by which biofilm bacteria liberate themselves from the matrix-encased biofilms and transition to the planktonic, free-living state that is less protected from the immune system, and more susceptible to antimicrobial agents.
To maintain their three-dimensional, aggregated structure, biofilms require pyruvate to cope with the stressful, oxygen-limiting but electron-rich conditions.
Pyruvate dehydrogenase (acyl transferring) (e.g., E.C. 184.108.40.206) is the first component enzyme of pyruvate dehydrogenase complex (PDC)(E.C. 126.96.36.199 and E.C. 184.108.40.206). The pyruvate dehydrogenase complex contributes to transforming pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, so pyruvate dehydrogenase contributes to linking the glycolysis metabolic pathway to the citric acid cycle and releasing energy via NADH. The pyruvate decarboxylase (PDC) mechanism with pyruvate (R=H) is shown in FIG. 19.
Formally, the reaction catalyzed is
pyruvate+[dihydrolipoyllysine-residue acetyltransferase] lipoyllysine→[dihydrolipoyllysine-residue acetyltransferase] S-acetyldihydrolipoyllysine+CO2
Other names for this enzyme are: MtPDC (mitochondrial pyruvate dehydrogenase complex); pyruvate decarboxylase; pyruvate dehydrogenase; pyruvate dehydrogenase (lipoamide); pyruvate dehydrogenase complex; pyruvate:lipoamide 2-oxidoreductase (decarboxylating and acceptor-acetylating); pyruvic acid dehydrogenase; pyruvic dehydrogenase.
See, Ochoa, S. Enzymic mechanisms in the citric acid cycle. Adv. Enzymol. Relat. Subj. Biochem. 15 (1954) 183-270; Scriba, P. and Holzer, H. Gewinnung von αHydroxyäthyl-2-thiaminpyrophosphat mit Pyruvatoxydase aus Schweineherzmuskel. Biochem. Z. 334 (1961) 473-486; Perham, R. N. Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annu. Rev. Biochem., 69, (2000) 961-1004. [PMID: 10966480], www.sbcs.qmul.ac.uk/iubmb/enzyme/EC1/2/4/1.html;
en.wikipedia.org/wiki/Pyruvate_dehydrogenase;
en.wikipedia.org/wiki/Pyruvate_dehydrogenase_complex.
In Gram-negative bacteria, e.g., Escherichia coli, PDC consists of a central cubic core made up from 24 molecules of dihydrolipoyl transacetylase (E2). Up to 24 copies of pyruvate dehydrogenase (E1) and 12 molecules of dihydrolipoyl dehydrogenase (E3) bind to the outside of the E2 core. In contrast, in Gram-positive bacteria (e.g. Bacillus stearothermophilus) and eukaryotes the central PDC core contains 60 E2 molecules arranged into an icosahedron. Eukaryotes also contain 12 copies of an additional core protein, E3 binding protein (E3BP). Up to 60 E1 or E3 molecules can associate with the E2 core from Gram-positive bacteria binding is mutually exclusive. In eukaryotes E1 is specifically bound by E2, while E3 associates with E3BP. It is thought that up to 30 E1 and 6 E3 enzymes are present, although the exact number of molecules can vary in vivo and often reflects the metabolic requirements of the tissue in question.
Pyruvate dehydrogenase (E1) performs the first two reactions within the pyruvate dehydrogenase complex (PDC): a decarboxylation of substrate 1 (pyruvate) and a reductive acetylation of substrate 2 (lipoic acid). Lipoic acid is covalently bound to dihydrolipoamide acetyltransferase (E2), which is the second catalytic component enzyme of PDC. The reaction catalyzed by pyruvate dehydrogenase (E1) is considered to be the rate-limiting step for the pyruvate dehydrogenase complex (PDHc). See FIG. 19.
Phosphorylation of E1 by pyruvate dehydrogenase kinase (PDK) inactivates E1 and subsequently the entire complex. PDK is inhibited by dichloroacetic acid and pyruvate, resulting in a higher quantity of active, unphosphorylated PDH. Phosphorylation is reversed by pyruvate dehydrogenase phosphatase, which is stimulated by insulin, PEP, and AMP, but competitively inhibited by ATP, NADH, and Acetyl-CoA.
The ylide resonance form of thiamine pyrophosphate (TPP) begins by attacking the electrophilic ketone of pyruvate. See FIG. 20. The intermediate β-alkoxide then decarboxylates and the resulting enol is deprotonated on the carbon atom to form a stabilized 1,3-dipole involving a positively charged nitrogen atom of the thiamine heterocycle. This 1,3-dipole undergoes a reductive acetylation with lipoamide-E2.
Biochemical and structural data for E1 revealed a mechanism of activation of TPP coenzyme by forming the conserved hydrogen bond with glutamate residue (Glu59 in human E1) and by imposing a V-conformation that brings the N4′ atom of the aminopyrimidine to intramolecular hydrogen bonding with the thiazolium C2 atom. This unique combination of contacts and conformations of TPP leads to formation of the reactive C2-carbanion, eventually. After the cofactor TPP decarboxylates pyruvate, the acetyl portion becomes a hydroxyethyl derivative covalently attached to TPP.
E1 is a multimeric protein. Mammalian E1s, including human E1, are tetrameric, composed of two αand two βsubunits. Some bacterial E1s, including E1 from Escherichia coli, are composed of two similar subunits, each being as large as the sum of molecular masses of αand βsubunits.
E1 has two catalytic sites, each providing thiamine pyrophosphate (TPP) and magnesium ion as cofactors. The βsubunit binds magnesium ion and pyrophosphate fragment while the β-subunit binds pyrimidine fragment of TPP, forming together a catalytic site at the interface of subunits.
Initially, pyruvate and thiamine pyrophosphate (TPP or vitamin B1) are bound by pyruvate dehydrogenase subunits. The thiazolium ring of TPP is in a zwitterionic form, and the anionic C2 carbon performs a nucleophilic attack on the C2 (ketone) carbonyl of pyruvate. The resulting hemithioacetal undergoes decarboxylation to produce an acyl anion equivalent (see cyanohydrin or aldehyde-dithiane umpolung chemistry, as well as benzoin condensation). This anion attacks S1 of an oxidized lipoate species that is attached to a lysine residue. In a ring-opening SN2-like mechanism, S2 is displaced as a sulfide or sulfhydryl moiety. Subsequent collapse of the tetrahedral hemithioacetal ejects thiazole, releasing the TPP cofactor and generating a thioacetate on S1 of lipoate. The E1-catalyzed process is the rate-limiting step of the whole pyruvate dehydrogenase complex.
At this point, the lipoate-thioester functionality is translocated into the dihydrolipoyl transacetylase (E2) active site, where a transacylation reaction transfers the acetyl from the "swinging arm" of lipoyl to the thiol of coenzyme A. This produces acetyl-CoA, which is released from the enzyme complex and subsequently enters the citric acid cycle. E2 can also be known as lipoamide reductase-transacetylase.
The dihydrolipoate, still bound to a lysine residue of the complex, then migrates to the dihydrolipoyl dehydrogenase (E3) active site where it undergoes a flavin-mediated oxidation, identical in chemistry to disulfide isomerase. First, FAD oxidizes dihydrolipoate back to its lipoate resting state, producing FADH2. Then, a NAD+cofactor oxidizes FADH2 back to its FAD resting state, producing NADH.
The reaction tends to be irreversible, for example because of the decarboxylation. The enzyme has a high substrate affinity, and therefore can reduce pyruvate to very low levels.
Pyruvate can also be specifically depleted using other enzymes such as lactate dehydrogenase (LDH) that catalyzes the conversion of pyruvate (plus NADH) to lactate and NAD+. Pyruvate carboxylase catalyzes the conversion of pyruvate and CO2 to oxaloacetate, but is ATP dependent. Alanine transaminase produces alanine from pyruvate, and glutamate to α-ketoglutarate, in a reversible reaction. Pyruvate decarboxylase is TPP dependent, and produces acetaldehyde and CO2. E. coli has a pyruvic formate lyase enzyme that catalyzes the reaction acetyl-CoA+formate=CoA+pyruvate.
Other enzymes are available that degrade pyruvate, such as pyruvate oxidase (en.wikipedia.org/wiki/Pyruvate_oxidase)(EC 18.104.22.168) is an enzyme that catalyzes the reaction:pyruvate+phosphate+O2 H acetyl phosphate+CO2+H2O2
The 3 substrates of this enzyme are pyruvate, phosphate, and O2, whereas its 3 products are acetyl phosphate, CO2, and H2O2. This enzyme belongs to the family of oxidoreductases, specifically those acting on the aldehyde or oxo group of donor with oxygen as acceptor. It has 2 cofactors: FAD, and Thiamin diphosphate.
See, Caiazza N C, O'Toole G A. 2004. SadB is required for the transition from reversible to irreversible attachment during biofilm formation by Pseudomonas aeruginosa PA14. J. Bacteriol. 186:4476-4485.
Models of biofilm formation by Pseudomonas aeruginosa propose that (i) planktonic cells become surface associated in a monolayer, (ii) surface-associated cells form microcolonies by clonal growth and/or aggregation, (iii) microcolonies transition to a mature biofilm comprised of exopolysaccharide-encased macrocolonies, and (iv) cells exit the mature biofilm and reenter the planktonic state.
Pseudomonas aeruginosa is a model organism for studying biofilm formation in gram-negative bacteria. Planktonic (free-swimming) P. aeruginosa initiates surface colonization in a flagellum-dependent manner, then forms transient ("reversible") surface interactions, and subsequently becomes firmly ("irreversibly") attached. It has been recently demonstrated for P. fluorescens that an ABC transporter and a large secreted protein are necessary for irreversible attachment by this organism. The earliest events in the pathway whereby planktonic bacteria form surface-associated microbial communities are unclear; however, it is clear that bacteria sample surface niches via reversible attachment before taking up permanent residence. This commitment to irreversible attachment is a crucial step in biofilm formation because initial surface colonizers are likely the foundation upon which the mature biofilm will be built. After irreversibly attaching, P. aeruginosa proceeds to form microcolonies in a type IV pilus and a GacA-dependent manner. As microcolonies become matrix-enclosed macrocolonies, cell-to-cell signaling is thought to become increasingly important. It has been proposed that this transition from a planktonic to a biofilm lifestyle is a developmental process.
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Dispersion inducers and quorum sensing factors may include various factors, such as ATP, c-di-GMP, other cyclic nucleotides, cis-2-decenoic acid, Skyllamycins A to C, nitric oxide, diphenyl selenide, etc.
Known antimicrobial agent include (poly)peptides, amikacin, aminoglycosides, amoxicillin, amoxicillin/clavulanate, amphotericin B, ampicillin, ampicillin-sulbactam, anidulafungin, ansamycins, arsphenamine, azithromycin, azlocillin, aztreonam, bacitracin, bacteriocins, bismuth thiols, carbacephems, carbapenems, carbenicillin, caspofungin, cefaclor, cefadroxil, cefalotin, cefamandole, cefazolin, cefdinir, cefditoren, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftaroline, ceftazidime, ceftibuten, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cephalexin, cephalosporins, chloramphenicol, ciprofloxacin, clarithromycin, clindamycin, clofazimine, cloxacillin, colicins, colistin, dalbavancin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doripenem, doxycycline, enoxacin, ertapenem, erythromycin, ethambutol, fecluroxime, flucloxacillin, fluconazole, flucytosine, fosfomycin, furazolidone, gatifloxacin, gemifloxacin, gentamicin, glycopeptides, grepafloxacin, imipenem, imipenem/cilastatin, isoniazid, itraconazole, kanamycin, ketoconazole, levofloxacin, lincomycin, lincosamides, linezolid, lomefloxacin, loracarbef, macrolides, mafenide, meropenem, metronidazole, mezlocillin, micafungin, microcins, minocycline, moxifloxacin, mupirocin, nafcillin, naldixic acid, neomycin, netilmicin, nitrofurans, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxazolidinones, oxycycline, oxytetracycline, paromomycin, penicillins, piperacillin, piperacillin-tazobactam, polymyxin B, polypeptides, posaconazole, posizolid, prontosil, pyrazinamide, quinolones, quinupristin/dalfopristin, radezolid, rifampicin, rifampin, rifaximin, roxithromycin, sparfloxacin, spectinomycin, spiramycin, streptomycin, suflonamides, sulfacetamide, sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfasalazine, sulfisoxazole, sulfonamides, teicoplanin, telavancin, telithromycin, temafloxacin, tetracyclines, ticarcillin, ticarcillin/clavulanate, tigecycline, tobramycin, torezolid, trimethoprim, trimethoprim-sulfamethoxazole, trovafloxacin, vancomycin, and voriconazole.
Known antibiofilm agents include: 6086921; 6106854; 6248371; 6641739; 6692757; 6793900; 6887270; 6908912; 7025986; 7052614; 7087661; 7144992; 7147888; 7151139; 7189329; 7189351; 7201925; 7217425; 7255881; 7314857; 7399742; 7402722; 7419607; 7427416; 7446089; 7450228; 7452345; 7556807; 7601731; 7628929; 7691418; 7744555; 7760353; 7781166; 7790947; 7794698; 7829305; 7863029; 7897631; 7906544; 7927496; 7993390; 7998919; 8071540; 8076117; 8105520; 8133501; 8142764; 8153119; 8153410; 8153412; 8162924; 8168072; 8173673; 8211361; 8216173; 8227017; 8231686; 8236545; 8246691; 8257827; 8267883; 8273104; 8278340; 8282593; 8282967; 8309590; 8318180; 8329758; 8343086; 8343911; 8349368; 8366652; 8367713; 8367716; 8367823; 8377455; 8383101; 8383582; 8389021; 8389679; 8398705; 8399235; 8399649; 8414517; 8415159; 8425880; 8431151; 8444858; 8460229; 8460916; 8461106; 8476425; 8481138; 8486428; 8501969; 8507244; 8545951; 8546121; 8552147; 8552208; 8569449; 8574660; 8585627; 8591876; 8591961; 8592473; 8609110; 8617523; 8617542; 8618149; 8623340; 8632838; 8637090; 8641686; 8647292; 8652829; 8653124; 8658225; 8680072; 8680148; 8684732; 8685427; 8685957; 8691264; 8697102; 8697375; 8702640; 8706211; 8709342; 8710082; 8715733; 8728467; 8734718; 8741855; 8753304; 8753692; 8754039; 8758781; 8778370; 8778387; 8778889; 8779023; 8785399; 8795727; 8796252; 8802059; 8802414; 8808718; 8809031; 8809314; 8821862; 8821910; 8828910; 8829053; 8835644; 8840912; 8846008; 8846009; 8846605; 8852912; 8853278; 8865909; 8884022; 8888731; 8889196; 8906349; 8906364; 8906393; 8906898; 8906915; 8920826; 8926951; 8927029; 8940911; 8945142; 8952192; 8956658; 8956663; 8962029; 8962283; 8968753; 8968765; 8981139; 8992223; 8999265; 9005263; 9005643; 9028878; 9029318; 9034346; 9034927; 9044485; 9045550; 9056899; 9073884; 9078441; 9084423; 9085608; 9096703; 9125408; 9125853; 9139622; 9145395; 9149648; 9150453; 9156855; 9161923; 9161984; 9167820; 9169319; 9180157; 9180158; 9181290; 9187501; 9198957; 9220267; 9221765; 9221875; 9227980; 9242951; 9247734; 9253987; 9265820; 9271493; 9271502; 9273096; 9283283; 9284351; 9289442; 9289449; 9295257; 9308298; 9320740; 9321030; 9326511; 9326924; 9326925; 9334466; 9339525; 9351491; 9351492; 9358274; 9364491; 9370187; 9376430; 9387189; 9402394; 9403851; 9403852; 9408393; 9415144; 9423532; 9427605; 9433527; 9439433; 9439436; 9439803; 9446090; 9452107; 9469616; 9474831; 9480260; 9480541; 9487453; 9492596; 9499594; 9504688; 9504739; 9518013; 9526738; 9526766; 9539233; 9539367; 9539373; 9540471; 9550005; 9554971; 9556109; 9556223; 9561168; 9562085; 9562254; 9565857; 9566247; 9566341; 9566372; 9574185; 9586871; 9592299; 9592324; 9597407; 9603859; 9603877; 9603977; 9603979; 9612246; 9617176; 9622481; 9631100; 9642829; 9644194; 9648876; 9657132; 9669001; 9669041; 9675077; 9675736; 9682023; 9683197; 9687670; 9694114; 9700058; 9700650; 9706778; 9713631; 9713652; 9717251; 9717765; 9718739; 9723833; 9723837; 9723843; 9724353; 9732124; 9737561; 9737571; 9737591; 9744270; 9757397; 9764069; 9770418; 9777050; 9782388; 9782423; 9789005; 9795762; 9801982; 9808496; 9814719; 9815794; 9833528; 9834744; 9839219; 9849182; 9850322; 9854807; 9855211; 9856225; 9861701; 9861723; 9862837; 9867906; 9872491; 9872893; 9872906; 9872917; 9877983; 9889077; 9895469; 9907584; 9914750; 9918473; 9919012; 9919072; 9919079; 9926526; 9931300; 9931381; 9932484; 9937104; 9956319; 9956322; 9975857; 20020066702; 20020123077; 20030065292; 20030079758; 20030091641; 20030099602; 20030103912; 20030111420; 20030121868; 20030134783; 20030178044; 20040110738; 20040116371; 20040116845; 20040129112; 20040131698; 20040156883; 20040156884; 20040176312; 20040191329; 20040254545; 20050003725; 20050013836; 20050032093; 20050049181; 20050064019; 20050143286; 20050147719; 20050158263; 20050202424; 20050233950; 20050249695; 20060001865; 20060018945; 20060034782; 20060067951; 20060110456; 20060120916; 20060138058; 20060162014; 20060177384; 20060180552; 20060224103; 20060243297; 20070009566; 20070010856; 20070020309; 20070062884; 20070083156; 20070098651; 20070098674; 20070098745; 20070106232; 20070109535; 20070116750; 20070116798; 20070134649; 20070190090; 20070202770; 20070224161; 20070231406; 20070232167; 20070244059; 20070258913; 20080014247; 20080014278; 20080014286; 20080044491; 20080050452; 20080075730; 20080085282; 20080085866; 20080107707; 20080109017; 20080113001; 20080138634; 20080181923; 20080206183; 20080206305; 20080248087; 20080268189; 20080286847; 20080293607; 20080318268; 20080318269; 20090033930; 20090048324; 20090050575; 20090069406; 20090074825; 20090099533; 20090112186; 20090133810; 20090143230; 20090155215; 20090163964; 20090163965; 20090163977; 20090171263; 20090177139; 20090177254; 20090181106; 20090202516; 20090214603; 20090221704; 20090238923; 20090260632; 20090263438; 20090270475; 20090318382; 20090324574; 20100015245; 20100016767; 20100021587; 20100028396; 20100048446; 20100055086; 20100056415; 20100059433; 20100096340; 20100129297; 20100129466; 20100130450; 20100133114; 20100136072; 20100136143; 20100145412; 20100152101; 20100158966; 20100158967; 20100173366; 20100174346; 20100178268; 20100183738; 20100189706; 20100221198; 20100234792; 20100234793; 20100240017; 20100241048; 20100241049; 20100241050; 20100241051; 20100241052; 20100241053; 20100241054; 20100241055; 20100247374; 20100249692; 20100254967; 20100255178; 20100266716; 20100272768; 20100286198; 20100292629; 20100298208; 20100305062; 20100316643; 20100322903; 20110003001; 20110008402; 20110008786; 20110027252; 20110027384; 20110029076; 20110033520; 20110033882; 20110039761; 20110039762; 20110039763; 20110046041; 20110052664; 20110077192; 20110086101; 20110098323; 20110104179; 20110105376; 20110117158; 20110117160; 20110119774; 20110124716; 20110129454; 20110135621; 20110144566; 20110150819; 20110152176; 20110152750; 20110152751; 20110152752; 20110152789; 20110152790; 20110152978; 20110160643; 20110160644; 20110160681; 20110171123; 20110171189; 20110172704; 20110177048; 20110177049; 20110177050; 20110177111; 20110182873; 20110182874; 20110201692; 20110207816; 20110208021; 20110208023; 20110208026; 20110217544; 20110229586; 20110236453; 20110250290; 20110256187; 20110262511; 20110266724; 20110274730; 20110275518; 20110275912; 20110280920; 20110281921; 20110294668; 20110295088; 20110295089; 20110295090; 20110301076; 20110305872; 20110305881; 20110305895; 20110305898; 20110305909; 20110306699; 20110311647; 20110319808; 20120010187; 20120010481; 20120015870; 20120020896; 20120039945; 20120040030; 20120041285; 20120041286; 20120041287; 20120045817; 20120052052; 20120058076; 20120058167; 20120058169; 20120058933; 20120077736; 20120087887; 20120088671; 20120094007; 20120107258; 20120122729; 20120128599; 20120129794; 20120134951; 20120135925; 20120136323; 20120142583; 20120149631; 20120150119; 20120152149; 20120156645; 20120157548; 20120160779; 20120171129; 20120178971; 20120189682; 20120201869; 20120209090; 20120213697; 20120219638; 20120225098; 20120238644; 20120244126; 20120252101; 20120258089; 20120258141; 20120283174; 20120288566; 20120288571; 20120294900; 20120301433; 20120308632; 20120315260; 20120321566; 20120328577; 20120328671; 20120328683; 20120328684; 20120328708; 20120328713; 20120329675; 20120329746; 20130005029; 20130022578; 20130029981; 20130039978; 20130045182; 20130052250; 20130058983; 20130059096; 20130059113; 20130059929; 20130071439; 20130095184; 20130101678; 20130101963; 20130102679; 20130108708; 20130110162; 20130123225; 20130123319; 20130129768; 20130129795; 20130129800; 20130131575; 20130136730; 20130136782; 20130149542; 20130150451; 20130158127; 20130158488; 20130158517; 20130158518; 20130164228; 20130164363; 20130165595; 20130171210; 20130171224; 20130171228; 20130172187; 20130183435; 20130190699; 20130196365; 20130197455; 20130210708; 20130220331; 20130224258; 20130224260; 20130225675; 20130231302; 20130252818; 20130252945; 20130266522; 20130266629; 20130267471; 20130281503; 20130287860; 20130287861; 20130309219; 20130310346; 20130315874; 20130315967; 20130330386; 20130330388; 20130337088; 20130344542; 20130345261; 20140005605; 20140020138; 20140023691; 20140037688; 20140037967; 20140039195; 20140039357; 20140056951; 20140056952; 20140056993; 20140057324; 20140065200; 20140072525; 20140073560; 20140073690; 20140079741; 20140079808; 20140105986; 20140107071; 20140120052; 20140127273; 20140128313; 20140142028; 20140147481; 20140155318; 20140155478; 20140161728; 20140161772; 20140161845; 20140170238; 20140171438; 20140172117; 20140186318; 20140187666; 20140193489; 20140194594; 20140205586; 20140205643; 20140212828; 20140221331; 20140221610; 20140223602; 20140228327; 20140234380; 20140241997; 20140242023; 20140243725; 20140255318; 20140257482; 20140271763; 20140271777; 20140276253; 20140276254; 20140277301; 20140288007; 20140288171; 20140294907; 20140302113; 20140308217; 20140308317; 20140308361; 20140322351; 20140322362; 20140328887; 20140328890; 20140328895; 20140328999; 20140335144; 20140342954; 20140348780; 20140349917; 20140350017; 20140357592; 20140370078; 20140371171; 20150005228; 20150011504; 20150018284; 20150018330; 20150024000; 20150024017; 20150024052; 20150031738; 20150038512; 20150038705; 20150044147; 20150044260; 20150045515; 20150050717; 20150056411; 20150080289; 20150080290; 20150086561; 20150086631; 20150087573; 20150087582; 20150099020; 20150110898; 20150111813; 20150118219; 20150132352; 20150147775; 20150148286; 20150148612; 20150157542; 20150159180; 20150165095; 20150166706; 20150166796; 20150167046; 20150173883; 20150182667; 20150183746; 20150190447; 20150197558; 20150209393; 20150224220; 20150225458; 20150225488; 20150231045; 20150231287; 20150237870; 20150238543; 20150246995; 20150259390; 20150274639; 20150283208; 20150283287; 20150297478; 20150297642; 20150299298; 20150299345; 20150315253; 20150322272; 20150327552; 20150332151; 20150335013; 20150335027; 20150336855; 20150351383; 20150351392; 20150368480; 20150374634; 20150374658; 20150374720; 20160008275; 20160009733; 20160010137; 20160015047; 20160021882; 20160022564; 20160022595; 20160022707; 20160024551; 20160030327; 20160031941; 20160038572; 20160038650; 20160058675; 20160058693; 20160058772; 20160058816; 20160058834; 20160058998; 20160067149; 20160073638; 20160074345; 20160075749; 20160089481; 20160096865; 20160106107; 20160106689; 20160107126; 20160109401; 20160120184; 20160122697; 20160128335; 20160129078; 20160135463; 20160135469; 20160137563; 20160137564; 20160137565; 20160157497; 20160158169; 20160158353; 20160166712; 20160176815; 20160184485; 20160185630; 20160186147; 20160193344; 20160194288; 20160198994; 20160199295; 20160206575; 20160212996; 20160213001; 20160220722; 20160223553; 20160235698; 20160235893; 20160235894; 20160237145; 20160242413; 20160249612; 20160256484; 20160262384; 20160263225; 20160270411; 20160278375; 20160279191; 20160279314; 20160280772; 20160289272; 20160289287; 20160304886; 20160309711; 20160317611; 20160317618; 20160324531; 20160330962; 20160338993; 20160339071; 20160346115; 20160346161; 20160346436; 20160353739; 20160355487; 20160375034; 20160375074; 20160376449; 20170007733; 20170009084; 20170014208; 20170014437; 20170020139; 20170022165; 20170022371; 20170028106; 20170029363; 20170035955; 20170042965; 20170043111; 20170044222; 20170049113; 20170050893; 20170050927; 20170056297; 20170056405; 20170056437; 20170056454; 20170056455; 20170056565; 20170064966; 20170065564; 20170065673; 20170071212; 20170071986; 20170072024; 20170072098; 20170073706; 20170080130; 20170095502; 20170100328; 20170100348; 20170100512; 20170100513; 20170100514; 20170100515; 20170100516; 20170100517; 20170100518; 20170100522; 20170100523; 20170106188; 20170107250; 20170112723; 20170113038; 20170119915; 20170127683; 20170128338; 20170128502; 20170128720; 20170135342; 20170137380; 20170143842; 20170150724; 20170156321; 20170158727; 20170173186; 20170182205; 20170189556; 20170197028; 20170202752; 20170216094; 20170216197; 20170216369; 20170216377; 20170216410; 20170224748; 20170232038; 20170232048; 20170232153; 20170240618; 20170246205; 20170246341; 20170247409; 20170247414; 20170252320; 20170258963; 20170266239; 20170266306; 20170273301; 20170274082; 20170280725; 20170281570; 20170281699; 20170283763; 20170290789; 20170290854; 20170295784; 20170296599; 20170297055; 20170312307; 20170312345; 20170326054; 20170333455; 20170333601; 20170339962; 20170340779; 20170347661; 20170347664; 20170360534; 20170360982; 20170367933; 20180000993; 20180008533; 20180008742; 20180014974; 20180014975; 20180015061; 20180016311; 20180021463; 20180028417; 20180028701; 20180028713; 20180030403; 20180030404; 20180030405; 20180030406; 20180036286; 20180036702; 20180037545; 20180037613; 20180042789; 20180042928; 20180043190; 20180049856; 20180051061; 20180079757; 20180079912; 20180085335; 20180085392; 20180085489; 20180085717; 20180092939; 20180093011; 20180105792; 20180110228; 20180111893; 20180112068; 20180119235; 20180125066; 20180125070; and 20180133326.
Enzyme encapsulation technologies include: 4006056; 4183960; 4257884; 4310554; 4342826; 4401122; 4418148; 4431428; 4458686; 4463090; 4483921; 4622294; 4666830; 4693970; 4756844; 4783400; 4861597; 4863626; 4876039; 4898781; 4900556; 4933185; 4963368; 4965012; 5015483; 5064669; 5068198; 5089278; 5093021; 5139803; 5147641; 5167854; 5190762; 5200236; 5200334; 5225102; 5230822; 5254287; 5258132; 5262313; 5272079; 5275154; 5281355; 5281356; 5281357; 5296231; 5324436; 5352458; 5385959; 5413804; 5434069; 5437331; 5441660; 5492646; 5505713; 5506271; 5523232; 5538511; 5545519; 5589370; 5604186; 5665380; 5693513; 5698083; 5752981; 5753152; 5777078; 5788678; 5830663; 5846927; 5858117; 5858430; 5861366; 5868720; 5895757; 5929214; 6017528; 6022500; 6051541; 6127499; 6197739; 6209646; 6225372; 6242405; 6258771; 6280980; 6303290; 6313197; 6359031; 6362156; 6368619; 6369018; 6395299; 6495352; 6500463; 6541606; 6608187; 6630436; 6730212; 6730651; 6818594; 6833192; 6927201; 6943200; 6972278; 6974706; 6979669; 7008524; 7033980; 7034677; 7052913; 7060299; 7153407; 7171312; 7172682; 7195780; 7198785; 7201923; 7250095; 7267837; 7267958; 7285523; 7329388; 7351798; 7375168; 7427497; 7491699; 7553653; 7723056; 7736480; 7740821; 7750050; 7750135; 7763097; 7786086; 7811436; 7846747; 7858561; 7927629; 7939061; 7942201; 7998714; 8007724; 8007725; 8030092; 8043411; 8053554; 8066818; 8101562; 8178332; 8182746; 8226996; 8268247; 8297959; 8313757; 8318156; 8323379; 8329225; 8350004; 8354366; 8361239; 8393395; 8399230; 8404469; 8460907; 8546316; 8558048; 8568786; 8575083; 8617623; 8685171; 8709487; 8759270; 8796023; 8810417; 8834865; 8852880; 8877506; 8898069; 8927689; 8932578; 8951749; 8961544; 8974802; 8980252; 8992986; 9012378; 9024766; 9056050; 9068109; 9074195; 9084784; 9089498; 9102860; 9107419; 9109189; 9121017; 9125876; 9146234; 9187766; 9200265; 9222060; 9273305; 9321030; 9333244; 9339529; 9376479; 9393217; 9415014; 9441157; 9458448; 9464368; 9492515; 9511125; 9562251; 9580739; 9618520; 9631215; 9637729; 9687452; 9700519; 9708640; 9717688; 9738689; 9744141; 9744221; 9744247; 9765324; 9782358; 9789439; 9790254; 9895427; 9907755; 9909143; 9931302; 9931433; 9957540; 9968663; 9970000; 20010044483; 20020045582; 20020058027; 20020094367; 20020106511; 20030045441; 20030059449; 20030060378; 20030062263; 20030082238; 20030158344; 20030162284; 20030162293; 20030175239; 20030219491; 20040061841; 20040076681; 20040121926; 20040135684; 20040147427; 20040149577; 20040175429; 20040198629; 20040204915; 20040241205; 20040249082; 20040265835; 20050037374; 20050053954; 20050123529; 20050130845; 20050150762; 20050150763; 20050153934; 20050155861; 20050163714; 20050176610; 20050245418; 20050245419; 20050255543; 20060045904; 20060079454; 20060110494; 20060159671; 20060160134; 20060280799; 20070001156; 20070003607; 20070048855; 20070059779; 20070098807; 20070111329; 20070116671; 20070128714; 20070134812; 20070141096; 20070141217; 20070154466; 20070166285; 20070224273; 20070258894; 20070296099; 20080009434; 20080014622; 20080090276; 20080115945; 20080145477; 20080187487; 20080220487; 20080223722; 20080226623; 20080274092; 20080283242; 20080302669; 20080311177; 20090035381; 20090075845; 20090088329; 20090110741; 20090123553; 20090162337; 20090169677; 20090181874; 20090186077; 20090202836; 20090246318; 20090288826; 20090297592; 20090301885; 20090324476; 20100015635; 20100034799; 20100074933; 20100081849; 20100086983; 20100125046; 20100159508; 20100192986; 20100196986; 20100197548; 20100197549; 20100197550; 20100197551; 20100197552; 20100197553; 20100197554; 20100210745; 20100213062; 20100239559; 20100240116; 20100255100; 20100258116; 20100260857; 20100267594; 20100291162; 20100291828; 20100307744; 20100310612; 20100316571; 20100316620; 20110015088; 20110039164; 20110039314; 20110039751; 20110045517; 20110050431; 20110053173; 20110053283; 20110054938; 20110081394; 20110111425; 20110117623; 20110177982; 20110217363; 20110217368; 20110217553; 20110229565; 20110229580; 20110269029; 20110280853; 20110280854; 20110300201; 20110300623; 20120016217; 20120021964; 20120027848; 20120028872; 20120028873; 20120040429; 20120063276; 20120066851; 20120071379; 20120071383; 20120121570; 20120143027; 20120189703; 20120220025; 20120240961; 20120258149; 20120261256; 20120318515; 20120322713; 20130017148; 20130017610; 20130029894; 20130029895; 20130067669; 20130084312; 20130108737; 20130113129; 20130131701; 20130133102; 20130136728; 20130149357; 20130195948; 20130195985; 20130197100; 20130207042; 20130219643; 20130224172; 20130224828; 20130244301; 20130251786; 20130284637; 20130323223; 20130345099; 20140027655; 20140045241; 20140046181; 20140086988; 20140127184; 20140127305; 20140127778; 20140151042; 20140219980; 20140295520; 20140323330; 20140328801; 20140335148; 20140348815; 20150010453; 20150026840; 20150030641; 20150071894; 20150086521; 20150086599; 20150099289; 20150147308; 20150147311; 20150147365; 20150147786; 20150150955; 20150151248; 20150166975; 20150190530; 20150191607; 20150191681; 20150203799; 20150231589; 20150246104; 20150246105; 20150335589; 20150374798; 20150376594; 20160022592; 20160022598; 20160030532; 20160038608; 20160045576; 20160051484; 20160051697; 20160075976; 20160101058; 20160120956; 20160123925; 20160153025; 20160160195; 20160168559; 20160175634; 20160193307; 20160208202; 20160215242; 20160215243; 20160222068; 20160222372; 20160222437; 20160243262; 20160250304; 20160291000; 20160326215; 20160354313; 20160361361; 20170002481; 20170035891; 20170044472; 20170107461; 20170107523; 20170176453; 20170188604; 20170189501; 20170190951; 20170191005; 20170202934; 20170204316; 20170211023; 20170218315; 20170219601; 20170247493; 20170252413; 20170292063; 20170304489; 20170321160; 20170321161; 20170333360; 20170333363; 20170335244; 20170335255; 20170349818; 20170368155; 20180008549; 20180008550; 20180016569; 20180030390; 20180050115; 20180055777; 20180073046; and 20180104315.
Enzyme immobilization technologies are known. See:
Barbosa, Oveimar, Rodrigo Tones, Claudia Ortiz:, Angel Berenguer-Murcia, Rafael C. Rodrigues, and Roberto Fernandez-Lafuente. "Heterofunctional supports in enzyme immobilization: from traditional immobilization protocols to opportunities in tuning enzyme properties." Biomacromolecules 14, no. 8 (2013): 2433-2462.
Biró, Emese, Agnes Sz Németh, Csaba Sisak, Tivadar Feczkó, and János Gyenis. "Preparation of chitosan particles suitable for enzyme immobilization." Journal of Biochemical and Biophysical Methods 70, no. 6 (2008): 1240-1246.
Brady, Dean, and Justin Jordaan. "Advances in enzyme immobilisation." Biotechnology letters 31, no. 11 (2009): 1639.
Cantone, Sara, Valerio Ferrario, Livia Coric Cynthia Ebert, Diana Fattor, Patrizia Spizzo, and Lucia Gardossi. "Efficient immobilisation of industrial biocatalysts: criteria and constraints for the selection of organic polymeric carriers and immobilisation methods." Chemical Society Reviews 42, no. 15 (2013): 6262-6276.
Datta, Sumitra, L. Rene Christena, and Yamuna Rani Sriramulu Rajaram. "Enzyme immobilization: an overview on techniques and support materials." 3 Biotech 3, no. 1 (2013):1-9.
Diaz, J. Felipe, and Kenneth J. Balkus Jr. "Enzyme immobilzation in MCM-41 molecular sieve." Journal of Molecular Catalysis B. Enzymatic 2, no. 2-3 (1996): 115-126.
DiCosimo, Robert, Joseph McAuliffe, Ayrookaran J. Poulose, and Gregory Bohlmann. "Industrial use of immobilized enzymes." Chemical Soc. Reviews 42, no. 15 (2013): 6437-6474.
Fernandez-Lafuente, Roberto. "Stabilization of multimeric enzymes: Strategies to prevent subunit dissociation." Enzyme and Microbial Technology 45, no. 6-7 (2009): 405-418.
Garcia-Galan, Cristina, Ángel Berenguer-Murcia, Roberto Fernandez-Lafuente, and Rafael C. Rodrigues. "Potential of different enzyme immobilization strategies to improve enzvtrle performance." Advanced Synthesis & Catalysis 353, no. 16 (2011): 2885-2904.
Guzik, Urszula, Katarzyna Hupert-Kocurek, and Danuta Wojcieszynska. "Immobilization as a strategy for improving enzyme properties-application to oxidoreductases," Molecules 19, no. 7 (2014): 8995-9018.
Homaei, Ahmad Abolpour, Reyhaneh Sariri, Fabio Vianello, and Roberto Stevanato. "Enzyme immobilization: an update." Journal of chemical biology 6, no. 4 (2013); 185-205.
Hwang, Fe lack, and Man Bock Gu. "Enzyme stabilization by nano/microsized hybrid materials." Engineering in Life Sciences 13, no. 1 (2013): 49-61.
Iyer, Padma V., and Laxmi Ananthanarayan. "Enzyme stability and stabilization aqueous and non-aqueous environment." Process biochemicstry 43, no. 10 (2008): 1019-1032.
Jesionowski, Teofil, Jakub Zdarta, and Barbara Krajewska. "Enzyme immobilization by adsorption: a review." Adsorption 20, no. 5-6 (2014): 801-821.
Juang, Ruey-Shin, Feng-Chin Wu, and Ru-Ling Tseng. "Use of chemically modified cliitosan beads for sorption and enzyme immobilization." Advances in Environmental Research 6, no. 2 (2002): 171-177.
Luckarift, Heather R., Jim C. Spain, Rajesh R. Naik, and Morley O. Stone. "Enzyme immobilization in a biomimetic silica support." Nature biotechnology 22, no. 2 (2004): 211.
Mateo, Cesar, Jose M. Palomo, Gloria Fernandez-Lorente, Jose M. Guisan, and Roberto Fernandez-Lafuente. "Improvement of enzyme activity, stability and selectivity via inamobilization techniques." Enzyme and microbial technology 40, no. 6 (2007): 1451-1463.
Paribasarothy, Ranjani V., and Charles R. Martin. "Synthesis of polymeric microcapsule arrays and their use for enzyme immobilization," Nature 369, no. 6478 (1994): 298.
Pierre, Sbbashen J. Jens C. Thies, Alex Dureault, Neil R. Cameron, pari C M van Hest, Noëlle Carette, Thierry Michon, and Ralf Weberskircli. "Covalent enzyme immobilization onto photopolyrnerized highly porous monoliths." Advanced Materials 18, no. 14 (2006): 1822-1826.
Pollak, Alfred, Hugh Blumenfeld, Michael Wax, Richard L. Baugh z, and George M. Whitesides. "Enzyme immobilization by condensation copolymerization into crosslinked polyacrylamide gels." Journal of the American Chemical Society 102 no. 20 (1980): 6324-6336.
Qhobosheane, Monde, Swadeshmukul Santra, :hang, and Weihong Tan, "Biochemically functionalized silica nanoparticles." Analyst 126, no. 8 (2001): 1274-1278.
Rodrigues, Rafael C., Ángel Berenguer-Murcia, and Roberto Fernandez-Lafuente. "Coupling chemical modification and immobilization to improve the catalytic performance of enzymes." Advances Synthesis * Catalysis 353, no. 13 (2011): 2216-2238.
Rodrigues, Rafael C., Claudia Ortiz, Ángel Berenguer-Murcia, Rodrigo Tones, and Roberto Fernandez-Lafuente. "Modifying enzyme activity and selectivity by immobilization." Chemical Society Reviews 42, no. 15 (2013): 6290-6307.
Sheldon, Roger A. "Enzyme immobilization: the quest For optimum performance." Advances Synthesis & Catalysis 349, no. 8-9 (2007): 1289-1307.
Sheldon, Roger A., and Sander an Pelt, "Enzyme immobilisation in biocatalysis: why, what and how." Chemical Soceity Reviews 42, no, 15 (2013): 6223-6235.
Spahn, Cynthia, and Shelley D. Minteer. "Enzyme immobilization in biotechnology." Recent patents on engineering 2, no. 3 (2008): 195-200.
Taqieddin, Ehab, and Mansoor Amiji. "Enzyme immobilization in novel alginate-chitosan core-shell microcapsules." Biomaterials 25, no. 10 (2004): 1937-1945.
Wang, Zhen-Gang, Ling-Shu Wan, Zhen-Mei Liu, Xiao-Jun Huang, and Zhi-Kang Xu. "Enzyme mmobilization electrospun polymer nanofibers: an overview." Journal of Molecular Catalysis B. Enzymatic 56, no. 4 (2009): 189-195.
The following enzymes are known to adversely impact biofilms:
Proteases:
Aureolysin (Aur)
LapG Protease
Pronase
Proteinase K
Savinase
Spl Proteases
Staphopain A (ScpA)1 Staphopain B (SspB)
Streptococcal Cysteine Protease (SpeB)
Surface-protein-releasing enzyme (SPRE)
Trypsin
V8 Serine Protease (SspA)
DNases
DNase I
DNase 1L2
Dornase alpha
λ Exonuclease
NucB
Streptodornase
Glycoside Hydrolases
Alginate lyase
α-amylase
α-mannosidase
β-mannosidase
Cellulase
Dispersin B
Hyaluronidase
PelAh
PslGH
Qurom-Sensing Signal-Degrading Enzymes
Acylase
Lactonase
Combinations
Glucose oxidase+lactoperoxidase
Acylase I+proteinase K
Cellulase+pronase

Compositions and methods for disrupting biofilm formation and maintenance

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