Mechanism of action of oritavancin and related glycopeptide antibiotics

Abstract

Oritavancin (LY333328) is a semisynthetic glycopeptide antibiotic having excellent bactericidal activity against glycopeptide-susceptible and -resistant Gram-positive bacteria. Oritavancin is the N-alkyl-p-chlorophenylbenzyl derivative of chloroeremomycin (LY264826) and is currently in phase III clinical trials for use in Gram-positive infections. Studies show that oritavancin and related alkyl glycopeptides inhibit bacterial cell wall formation by blocking the transglycosylation step in peptidoglycan biosynthesis in a substrate-dependent manner. As with other glycopeptide antibiotics, including vancomycin, the effects of oritavancin on cell wall synthesis are attributable to interactions with dipeptidyl residues of peptidoglycan precursors. Unlike vancomycin, however, oritavancin is strongly dimerized and can anchor to the cytoplasmic membrane, the latter facilitated by its alkyl side chain. Cooperative interactions derived from dimerization and membrane anchoring in situ can be of sufficient strength to enable binding to either dipeptidyl or didepsipeptidyl peptidoglycan residues of vancomycin-susceptible and -resistant enterococci, respectively. This review describes the antibacterial activity of oritavancin, and examines the evidence supporting the proposed mechanism of action for this agent and related analogs.