Oritavancin exhibits dual mode of action to inhibit cell-wall biosynthesis in Staphylococcus aureus.
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Kim SJ, Cegelski L, Stueber D, Singh M, Dietrich E, Tanaka KS, Parr TR Jr, Far AR, Schaefer J
Oritavancin exhibits dual mode of action to inhibit cell-wall biosynthesis in Staphylococcus aureus.
J Mol Biol. 2008 Mar 14;377(1):281-93. doi: 10.1016/j.jmb.2008.01.031. Epub 2008 Jan 17.
- PubMed ID
- 18258256 [ View in PubMed]
- Abstract
Solid-state NMR measurements performed on intact whole cells of Staphylococcus aureus labeled selectively in vivo have established that des-N-methylleucyl oritavancin (which has antimicrobial activity) binds to the cell-wall peptidoglycan, even though removal of the terminal N-methylleucyl residue destroys the D-Ala-D-Ala binding pocket. By contrast, the des-N-methylleucyl form of vancomycin (which has no antimicrobial activity) does not bind to the cell wall. Solid-state NMR has also determined that oritavancin and vancomycin are comparable inhibitors of transglycosylation, but that oritavancin is a more potent inhibitor of transpeptidation. This combination of effects on cell-wall binding and biosynthesis is interpreted in terms of a recent proposal that oritavancin-like glycopeptides have two cell-wall binding sites: the well-known peptidoglycan D-Ala-D-Ala pentapeptide stem terminus and the pentaglycyl bridging segment. The resulting dual mode of action provides a structural framework for coordinated cell-wall assembly that accounts for the enhanced potency of oritavancin and oritavancin-like analogues against vancomycin-resistant organisms.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Oritavancin Bacterial cell wall peptide bridging segments Group Staphylococcus aureus YesInhibitorDetails Oritavancin Pentaglycyl bridging segment Group Staphylococcus aureus YesDisruptorDetails Oritavancin Peptidoglycan precursors Group YesBinderDetails