While β-lactams have been highly successful antibiotics, their widespread use has led to antibiotic resistance. β-Lactamses, a family of hydrolytic enzymes that inactivate all β-lactams, are of particular concern due to high catalytic efficiency and rapid distribution via horizontal transfer on plasmids. β-Lactamase inhibitors (sulbactam, clavulanate, tazobactam, avibactam, and vaborbactam) have little antibacterial activity by themselves but can inactivate β-lactamases to restore the antibacterial activity of β-lactams. More recently, compounds incorporating two βlactam groups have been developed as dual β-lactamase inhibitors and antibiotics to circumvent drug resistance. Combining a β-lactam moiety with another class of antibiotic is another approach. For example, TD-1792 (Cefilavancin) is a novel covalently linked heterodimer of a glycopeptide (vancomycin) and a cephalosporin for the treatment of serious Gram-positive infections like acute bacterial skin and skin structure infection; it has completed phase II clinical trials in the US and is currently under the filling process in Russia. Another approach is conjugating β-lactams to bacterial transporters like siderophores. A successful example of this is Cefiderocol, a siderophore-containing cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli that is currently available commercially under the brand name Fetroja for the treatment of complicated urinary tract infections. Aminoglycosides: The isolation of the first aminoglycoside with antibiotic properties, streptomycin, was first reported in 1944. It was isolated from two strains of actinomyces related to Streptomyces griseus. Since then, many have been obtained via the fermentation of Streptomyces (neomycin from S. fradiae , kanamycin from S. kanamyceticus , tobramycin from S. tenebrarius ) and Micromonospora (gentamicin Micromonospora purpurea , sisomicin from Micromonospora inyoensis ) or through chemical modification of aminoglycoside scaffolds (amikacin , netilmicin , arbekacin , plazomicin ). Aminoglycosides are hydrophilic molecules that have one or more aminated sugars joined in glycosidic linkages to a dibasic cyclitol (aminocyclitol), which is most commonly a 2deoxystreptamine. They can be classified into two broad categories based on the aminocyclitol moiety: those with a deoxystreptamine ring and those without (streptomycin). This first category can be further divided based on the substitution of the deoxystreptamine ring: monosubstituted (apramycin), 4,5-di-substituted (neomycin, ribostamycin), and 4,6-di-substituted (gentamicin, amikacin, tobramycin, and plazomicin). This family of molecules is bactericidal and has a broad spectrum of activity against Gram-negative and Gram-positive bacteria, being particularly potent against Enterobacteriacae. They inhibit bacterial protein synthesis via binding to prokaryotic ribosomes. The primary mechanism of action is via binding to the 16S ribosomal RNA at the tRNA acceptor aminoacyl-site (A-site) on the 30S ribosome, altering the conformation of the A-site. This inhibits the translation process by causing codon misreading and/or by hindering the translocation of tRNA from the A-site to the peptidyl tRNA, causing defective protein synthesis that can cause damage to the cell. Some aminoglycosides can also block the elongation of translation or directly inhibit initiation. The most prevalent resistance mechanism is the enzymatic modification caused by aminoglycoside modifying enzymes, specifically by aminoglycoside acyltransferases (AACs), aminoglycoside phosphotransferases (APHs), and aminoglycoside nucleotransferases (ANTs). Other resistance mechanisms are target site modification via methylation of 16S rRNA or chromosomal mutation; efflux, uptake and permeability mutations; and highly efficient membrane proteases. Strategies to combat this resistance, as well as new developments in these strategies have been discussed by Becker and Cooper, Krause et al. and Tevyashova and Shapovalova. In addition to resistance, adverse effects like ototoxicity, nephrotoxicity, and in some cases, neuromuscular blockade are also an issue. Decreasing the associated toxicities is also a focus when it comes to developing new derivatives. Tetracyclines: Tetracyclines are a broad-spectrum bacteriostatic antibiotic class whose structure is based on a DCBA naphthacene core. Aureomycin, 6-chlorotetracycline, was the first member of this antibiotic class to be reported, discovered by Benjamin Minge Duggar at Lederle Laboratories in 1948. This was followed by terramycin, reported in 1950 and discovered by Alexander Finley from Pfizer. 110 These first tetracyclines were natural products obtained from Streptomyces from soil samples, specifically via fermentation of Streptomyces aureofaciens (aureomycin) and Streptomyces rismosus (terramycin). Additional natural product tetracyclines are tetracycline (Teracyn) and demeclocycline, while other members of this class are semisynthetic tetracyclines (lymecycline, methacycline, minocycline, rolitetracycline, sarecycline, omadacycline and doxycycline), glycylcyclines (tigecycline), and synthetic tetracyclines (eravacycline, TP-271). This class of antibiotics is effective against a wide range of Gram-positive and Gram-negative bacteria. Members of this family are effective against: Yersinia pestis, Vibrio cholera, Salmonella enterica, Treponema pallidum, Legionella pneumophila, Bacillus anthracis, Borrelia burgdoferi, Borrelia afzelii, Borrelia garinii, Borrelia recurrentis, Mycobacterium tuberculosis, Coxiella burnetii, Rickettsia ricketsii, Mycobacterium lepra, Mycobacterium marinum, Mycoplasma pneumoniae, Staphylococcus aureus (including MRSA), Vibrio vulnificus and vancomycin-resistant enterococcus. Their main mechanism of action is the inhibition of protein synthesis in bacteria. They bind reversibly to the A site of the 30S ribosomal unit, interfering with the binding of the aminoacyl-tRNA to the acceptor site of the mRNA-ribosome complex which prevents the addition of new amino acids to the growing peptides and impairs the cells' ability to grow or replicate. Still, bacterial resistance has developed via reduction of intracellular concentration by active efflux, disruption of the interaction with the 30s subunit by ribosomal protective proteins (TetM and TetO), deactivation via hydroxylation of position C-11a (TetX and Tet 37), and mutation of the binding site. Recent literature has further discussion on resistance, synthesis, photoactivation, new applications, modifications, and the new generation of tetracyclines. Polymyxins (Polymyxin B and Colistin): Polymyxins are lipopeptide antibiotics isolated from Paenibacillus polymyxa. They contain a peptide lactam macrocycle core with an attached peptide terminally substituted with a lipid acyl group; their diamino-butane carboxylate moieties contribute positive change under biological conditions, rendering the polymyxin antibiotics pentacationic. Two polymyxins, polymyxin B and colistin, are in clinical use. Polymyxin B (as its sulfate) is used to treat infections of the urinary tract, meninges (when administered intrathecally), and bloodstream and as a topical or subconjunctival agent for eye infections caused by susceptible strains of Pseudomonas aeruginosa. It may be used for serious meningeal or urinary tract infections or bacteremia by susceptible strains of Haemophilus influenzae, Escherichia coli, Aerobacter aerogenes, or Klebsiella pneumoniae if less toxic antibiotics are not effective. Colistin (as its penta-N-methanesulfonate prodrug) is used to treat acute or chronic infections due to sensitive strains of Pseudomonas aeruginosa, Enterobacter aerogenes, Escherichia coli, or Klebsiella pneumoniae (but not Proteus or Neisseria species) . The polymyxins have limited activity against Acinetobacter, Pseudomonas aeruginosa, Klebsiella, and Escherichia coli species because of resistance. Acinetobacter species can exhibit heteroresistance, in which a drugresistant population coexists with a drug-susceptible population, making drug susceptibility testing difficult or impossible. The mechanism of polymyxin anti-bactericidal activity is not completely defined. The binding of polymyxins to negatively charged lipopolysaccharide phosphates in bacterial membranes disrupts their outer membranes, causing membrane-membrane contact and lipid exchange between membranes with consequent loss of membrane integrity (because Grampositive pathogens possess a cell wall that cannot be disrupted by polymyxins). Polymyxin also causes the buildup of reactive oxygen species in membranes, likely by inhibiting the inner membrane type II NADH-quinone oxidoreductase, which oxidizes and cleaves membrane lipids and further compromises bacterial membrane integrity. Finally, polymyxins bind to and inactivate endotoxins. Bacteria circumvent these mechanisms in a variety of ways. As for other antibacterial agents, efflux pumps can export polymyxins from bacteria. Bacteria modify their membranes to reduce their negative charge (and to hinder the binding affinity of cationic polymyxins) by incorporating amino group-containing components such as phosphoethanolamine and 4-amino-L-arabinose into lipopolysaccharides. The suppression of lipid A incorporation and replacement by amino-substituted components is controlled by the two-component system (TCS). 121 Bacteria also upregulate the production of proteins needed to maintain lipid asymmetry in the outer membrane. Acinetobacter baumanii can respond to polymyxins by removing lipid A from its membranes, preventing polymyxin binding; however, purging lipid A renders its membranes more permeable, making it susceptible to other antibiotics.