Wall Peptidoglycan Inhibitors

Vancomycin is bactericidal to most susceptible bacteria at concentrations near its minimum inhibitory concentration (MIC) and is an inhibitor of bacterial cell wall peptidoglycan synthesis, although at a site different from that of j3-lactam antibiotics (Chapter 9). 

Omura et al. (1979) describe a method for detecting specific inhibitors of cell wall peptidoglycan synthesis. The method is based on the inactivity of cell wall inhibitors against Mycoplasma, which lack a cell wall, and on inhibition of the incorporation of mc5o-diaminopimelic acid into the acid-insoluble macromolecular fraction of Bacillus. 

The glycopeptides are inhibitors of cell wall synthesis. They bind to the terminal carboxyl group on the d-alanyl-D-alanine terminus of the A-acetylglucosamine-A-acetylmuramic acid peptide and prevent polymerization of the linear peptidoglycan by peptidoglycan synthase. They are bactericidal in vitro. 

Another enzyme-activated inhibitor is the streptomyces antibiotic D-cycloserine (oxamycin), an antitubercular drug that resembles D-alanine in structure. A potent inhibitor of alanine racemase, it also inhibits die non-PLP, ATP-dependent, D-alanyl-D-alanine synthetase which is needed in the biosynthesis of die peptidoglycan of bacterial cell walls. 

As described in the first section of this chapter, D-alanine is an essential constituent of the peptidoglycan layer of bacterial cell wall, but it is not a common metabolite in mammalian cells. Therefore, alanine racemase has been recognized as a suitable target for antibiotics, and a variety of natural and synthetic inhibitors (inactivators) of the enzyme have been reported. 

Selective inhibition of bacterial cell wall synthesis (penicillins, cephalosporins, bacitracin, vancomycin). Following attachment to receptors (penicillinbinding proteins), p-lactam antibiotics inhibit transpeptidation enzymes and thereby block the final stage of peptidoglycan sysnthesis. This action is followed by inactivation of an inhibitor of autolytic enzymes in the bacterial cell wall. Bacitracin and vancomycin inhibit early stages of peptidoglycan synthesis. 

Fluoroquinolones inhibit bacterial topoisomerases II and IV Streptogramins are recently introduced inhibitors of bacterial nucleic acid synthesis Vancomycin inhibits the synthesis of precursors of the linear peptidoglycan chains of the bacterial cell wall... 

Early workers [29] found that, like benzylpenicillin, vancomycin, ristocetin and bacitracin, novobiocin caused an excessive accumulation of cell wall precursor, uridine diphosphate-7V-acetylmuramic acid-L-alanine-D-glutamic acid-L-lysine-D-alanine-D-alanine (UDP-MurNAc-L-ala-D-glu-L-lys-D-ala-D-ala) in Staph, aureus and it was thus considered that novobiocin was a specific inhibitor of peptidoglycan synthesis with an effect similar to that of penicillin. However, subsequent studies led to the withdrawal of this hypothesis [26], since novobiocin caused the accumulation of other precursor-type compounds and also strongly inhibited both nucleic acid and protein synthesis in this organism. Thus, accumulation of particular precursors does not necessarily reflect the site of action of an antibacterial agent [30]. 

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