Novobiocin is a pale yellow, somewhat photosensitive compound that crystallizes in two chemically identical forms with different melting points (polymorphs). It is soluble in methanol, ethanol, and acetone but is quite insoluble in less polar solvents. Its solubility in water is affected by pH. It is readily soluble in basic solutions, in which it deteriorates, and is precipitated from acidic solutions. It behaves as a diacid, forming two series of salts.
The enolic hydroxyl group on the coumarin moiety behaves as a rather strong acid (pKa 4.3) and is the group by which the commercially available sodium and calcium salts are formed. The phenolic -OH group on the benzamido moiety also behaves as an acid but is weaker than the former, with a pKa of 9.1. Disodium salts of novobiocin have been prepared. The sodium salt is stable in dry air but loses activity in the presence of moisture. The calcium salt is quite water insoluble and is used to make aqueous oral suspensions. Because of its acidic characteristics, novobiocin combines to form salt complexes with basic antibiotics. Some of these salts have been investigated for their combined antibiotic effect, but none has been placed on the market, as they offer no advantage.
The action of novobiocin is largely bacteriostatic. Its mode of action is not known with certainty, though it does inhibit bacterial protein and nucleic acid synthesis. Studies indicate that novobiocin and related coumarin-containing antibiotics bind to the subunit of DNA gyrase and possibly interfere with DNA supercoiling276 and energy transduction in bacteria.277 The effectiveness of novobiocin is confined largely to Gram-positive bacteria and a few strains of P. vulgaris. Its low activity against Gram-negative bacteria is apparently because of poor cellular penetration.
Although cross-resistance to other antibiotics is reported not to develop with novobiocin, resistant S. aureus strains are known. Consequently, the medical use of novobiocin is reserved for the treatment of staphylococcal infections resistant to other antibiotics and sulfas and for patients allergic to these drugs. Another shortcoming that limits the usefulness of novobiocin is the relatively high frequency of adverse reactions, such as urticaria, allergic rashes, hepato-toxicity, and blood dyscrasias.
Mupirocin (pseudomonic acid A, Bactroban) is the major component of a family of structurally related antibiotics, pseudomonic acids A to D, produced by the submerged fermentation of Pseudomonas fluorescens. Although the antimicrobial properties of P. fluorescens were recorded as early as 1887, it was not until 1971 that Fuller et al.278 identified the metabolites responsible for this activity. The structure of the major and most potent metabolite, pseudomonic acid A (which represents 90%-95% of the active fraction from P. fluorescens), was later confirmed by chemical synthesis279 to be the 9-hydroxynonanoic acid ester of monic acid.
The use of mupirocin is confined to external applications.280 Systemic administration of the antibiotic results in rapid hydrolysis by esterases to monic acid, which is inactive in vivo because of its inability to penetrate bacteria. Mupirocin has been used for the topical treatment of impetigo, eczema, and folliculitis secondarily infected by susceptible bacteria, especially staphylococci and ^-hemolytic streptococci. The spectrum of antibacterial activity of mupirocin is confined to Gram-positive and Gramnegative cocci, including staphylococci, streptococci, Neisseria spp., and M. catarrhalis. The activity of the antibiotic against most Gram-negative and Gram-positive bacilli is generally poor, with the exception of H. influen-zae. It is not effective against enterococci or anaerobic bacteria.
Mupirocin interferes with RNA synthesis and protein synthesis in susceptible bacteria.281,282 It specifically and re-versibly binds with bacterial isoleucyl tRNA synthase to prevent the incorporation of isoleucine into bacterial proteins.282 High-level, plasmid-mediated mupirocin resistance in S. au-reus has been attributed to the elaboration of a modified isoleucyl tRNA that does not bind mupirocin.283 Inherent resistance in bacilli is likely because of poor cellular penetration of the antibiotic.284
Mupirocin is supplied in a water-miscible ointment containing 2% of the antibiotic in polyethylene glycols 400 and 3350.
Quinupristin/dalfopristin (Synercid) is a combination of the streptogramin B quinupristin with the streptogramin A dalfopristin in a 30:70 ratio.
Both of these compounds are semisynthetic derivatives of two naturally occurring pristinamycins produced in fermentations of Streptomyces pristinaspiralis. Quinupristin and dalfopristin are solubilized derivatives of pristinamycin Ia and pristinamycin Ila, respectively, and therefore are suitable for intravenous administration only.
The spectrum of activity of quinupristin/dalfopristin is largely against Gram-positive bacteria. The combination is active against Gram-positive cocci, including S. pneumoniae, ^-hemolytic and ^-hemolytic streptococci, Enterococcus faecium, and coagulase-positive and coagulase-negative staphylococci. The combination is mostly inactive against Gram-negative organisms, although M. catarrhalis and Neisseria spp. are susceptible. The combination is bactericidal against streptococci and many staphylococci, but bacte-riostatic against E. faecium.
Quinupristin and dalfopristin are protein synthesis inhibitors that bind to the 50S ribosomal subunit. Quinupristin, a type B streptogramin, binds at the same site as the macrolides and has a similar effect, resulting in inhibition of polypeptide elongation and early termination of protein synthesis. Dalfopristin binds to a site near that of quinupristin. The binding of dalfopristin results in a conformational change in the 50S ribosomal subunit, synergis-tically enhancing the binding of quinupristin at its target site. In most bacterial species, the cooperative and synergistic binding of these two compounds to the ribosome is bactericidal.
Synercid should be reserved for the treatment of serious infections caused by multidrug-resistant Gram-positive organisms such as vancomycin-resistant E. faecium.
Linezolid (Zyvox) is an oxazolidinedione-type antibacterial agent that inhibits bacterial protein synthesis. It acts in the early translation stage, preventing the formation of a functional initiation complex. Linezolid binds to the 30S and 70S ribosomal subunits and prevents initiation complexes involving these subunits. Collective data suggest that the oxazo-lidindiones partition their ribosomal interaction between the two subunits. Formation of the early tRNAfMet-mRNA-70S or 30S is prevented. Linezolid is a newer synthetic agent, and hence, cross-resistance between the antibacterial agent and other inhibitors of bacterial protein synthesis has not been seen.
Linezolid possesses a wide spectrum of activity against Gram-positive organisms, including MRSA, penicillin-resistant pneumococci, and vancomycin-resistant Enterococcus faecalis and E. faecium. Anaerobes such as Clostridium, Peptostreptococcus, and Prevotella spp. are sensitive to linezolid.
Linezolid is a bacteriostatic agent against most susceptible organisms but displays bactericidal activity against some strains of pneumococci, B. fragilis, and Clostridium perfringens.
The indications for linezolid are for complicated and uncomplicated skin and soft-tissue infections, community-and hospital-acquired pneumonia, and drug-resistant Grampositive infections.
Fosfomycin tromethamine (Monurol) is a phosphonic acid epoxide derivative that was initially isolated from fermentations of Streptomyces spp. The structure of the drug is shown next. Making the tromethamine salt greatly expanded the therapeutic utility of this antibacterial because water solubility increased enough to allow oral administration.
Fosfomycin is a broad-spectrum, bactericidal antibacterial that inhibits the growth of E. coli, S. aureus, and Serratia, Klebsiella, Citrobacter, Enterococcus, and Enterobacter spp. at a concentration less than 64 mg/L. Currently fosfomycin is recommended as single-dose therapy for uncomplicated urinary tract infections. It possesses in vitro efficacy similar to that of norfloxacin and trimethoprim-sulfamethoxazole.
Fosfomycin covalently inactivates the first enzyme in the bacterial cell wall biosynthesis pathway, UDP-N-acetylglu-cosamine enolpyruvyl transferase (MurA) by alkylation of the cysteine-115 residue. The inactivation reaction occurs through nucleophilic opening of the epoxide ring. Resistance to fosfomycin can occur through chromosomal mutations that result in reduced uptake or reduced MurA affinity for the inhibitor. Plasmid-mediated resistance mechanisms involve conjugative bioinactivation of the antibiotic with glutathione. The frequency of resistant mutants in in vitro studies has been low, and there appears to be little cross-resistance between fosfomycin and other antibacterials.
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