title: Oritavancin: mechanism of action.
abstract: Oritavancin is a semisynthetic lipoglycopeptide analogue of vancomycin that contains the heptapeptide core common to all glycopeptides. It differs from vancomycin by the presence of a hydrophobic N-4-(4-chlorophenyl)benzyl (also referred to as 4'-chlorobiphenylmethyl) substituent on the disaccharide sugar, the addition of a 4-epi-vancosamine monosaccharide to the amino acid residue in ring 6, and the replacement of the vancosamine moiety by 4-epi-vancosamine. One mechanism of action of oritavancin is inhibition of transglycosylation (important in peptidoglycan synthesis) by binding to D-alanyl-D-alanine stem termini in Gram-positive bacteria. The inhibition of peptidoglycan synthesis via inhibition of transglycosylation is common to all glycopeptides (vancomycin) and lipoglycopeptides. Secondary binding of oritavancin to the pentaglycyl (Asp/Asn) bridging segment in peptidoglycan also occurs, which distinguishes it from vancomycin and contributes to oritavancin's activity versus vancomycin-resistant organisms. The presence of the hydrophobic 4'-chlorobiphenylmethyl group allows for interaction and disruption of the cell membrane, resulting in depolarization, permeabilization, and concentration-dependent, rapid cell death. This mechanism is shared with telavancin but not vancomycin and results in activity against daptomycin-nonsusceptible organisms. In conclusion, oritavancin's mechanism of action involves at least 3 known mechanisms: inhibition of transglycosylation, inhibition of transpeptidation, and cell membrane interaction/disruption. Oritavancin's multiple mechanisms of action confer activity against vancomycin-susceptible and -resistant organisms, as well as rapid, concentration-dependent killing versus actively growing, stationary phase, and biofilm-producing Gram-positive bacteria.
authors.affiliation: Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada. ggzhanel@pcs.mb.ca
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.forename: Frank
authors.initials: F
authors.lastname: Schweizer
authors.forename: James A
authors.initials: JA
authors.lastname: Karlowsky
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D016984:Enterococcus faecium / Q000187:drug effects; D006020:Glycopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006031:Glycosylation / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D000077427:Lipoglycopeptides; D010457:Peptidoglycan / Q000187:drug effects / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects; D014640:Vancomycin / Q000031:analogs & derivatives
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D000077427:Lipoglycopeptides; D010457:Peptidoglycan; C100708:oritavancin; D014640:Vancomycin