Comparison of the target sites and mechanisms of action of glycopeptide and lipoglycodepsipeptide antibiotics - PubMed (original) (raw)

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Comparative Study

Comparison of the target sites and mechanisms of action of glycopeptide and lipoglycodepsipeptide antibiotics

P E Reynolds et al. Drugs Exp Clin Res. 1990.

Abstract

In this brief review of glycopeptides (teicoplanin and vancomycin) and lipoglycodepsipeptides (ramoplanin), comparison is made of their structure, general mode of action, specific target site and the mechanism by which inhibition of the sensitive enzyme is achieved. Although these two groups of antibiotics are chemically very different, they both inhibit late stages in the biosynthesis of bacterial cell wall peptidoglycan and cause the accumulation of the identical cell wall precursor, UDP-MurNAc-pentapeptide, in the cytoplasm. The specific target site is at the level of the membrane-bound enzymes which catalyse the attachment of wall precursors to a lipid carrier and subsequent polymerisation: ramoplanin inhibits transfer of one of the two precursors, whereas the glycopeptides block polymerisation. As different targets are involved, cross-resistance between glycopeptides and ramoplanin is unlikely and has not yet been reported. The actual mechanisms of action are totally different: glycopeptides inhibit the sensitive reaction by binding firmly, as a result of substantial hydrogen bonding, to acyl-D-Ala-D-Ala termini of the nascent peptidoglycan chains or lipid-linked wall subunits. The substrate is sequestered in a cleft of the antibiotic molecule and cannot interact with the polymerase enzyme. The precise mechanism of action of ramoplanin has not been elucidated, but its action is not dependent on the presence of the acyl-D-Ala-D-Ala group in the substrate and its binding characteristics are different from those of the glycopeptides. It therefore has a different mechanism of action as well as a different site, compared with the glycopeptides.

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