Approved Glycopeptide Antibacterial Drugs: Mechanism of Action and Resistance

Abstract

The glycopeptide antimicrobials are a group of natural product and semisynthetic glycosylated peptides that show antibacterial activity against Gram-positive organisms through inhibition of cell-wall synthesis.This is achieved primarily through binding to the D- alanyl-D-alanine terminus of the lipid II bacterial cell-wall precursor, preventing crosslinking of the peptidoglycan layer.Vancomycin is the foundational member of the class, showing both clinical longevity and a still preferential role in the therapy of methicillinresistant Staphylococcus aureus and of susceptible Enterococcus spp.Newer lipoglycopeptide derivatives (telavancin, dalbavancin, and oritavancin) were designed in a targeted fashion to increase antibacterial activity, in some cases through secondary mechanisms of action.Resistance to the glycopeptides emerged in delayed fashion and occurs via a spectrum of chromosome-and plasmid-associated elements that lead to structural alteration of the bacterial cell-wall precursor substrates.T he glycopeptide antibiotics are a group of glycosylated cyclic or polycyclic nonribosomal peptides that inhibit Gram-positive bacterial cell-wall synthesis.Unlike other antimicrobial classes, these agents act as substrate binders (of cell-wall precursors) as opposed to active-site enzyme inhibitors (Barna and Williams 1984;Nagarajan 1994).Significant members of this class include vancomycin and the lipoglycopeptide teicoplanin, along with the semisynthetic lipoglycopeptide derivatives telavancin, dalbavancin, and oritavancin (Fig. 1).All Editors: Lynn L. Silver and Karen Bush