Oritavancin exhibits dual mode of action to inhibit cell-wall biosynthesis in Staphylococcus aureus.
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.
Kim
Sung Joon
SJ
Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130, USA.
Cegelski
Lynette
L
Stueber
Dirk
D
Singh
Manmilan
M
Dietrich
Evelyne
E
Tanaka
Kelly S E
KS
Parr
Thomas R
TR
Far
Adel Rafai
AR
Schaefer
Jacob
J
D000596:Amino Acids / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D002247:Carbon Isotopes; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005461:Fluorine; D006020:Glycopeptides / Q000378:metabolism / Q000494:pharmacology*; D000077427:Lipoglycopeptides; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D008958:Models, Molecular; D009587:Nitrogen Isotopes; D010457:Peptidoglycan / Q000096:biosynthesis / Q000737:chemistry; D013211:Staphylococcus aureus / Q000166:cytology* / Q000187:drug effects*; D014640:Vancomycin / Q000031:analogs & derivatives
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D002247:Carbon Isotopes; D003432:Cross-Linking Reagents; D005461:Fluorine; D006020:Glycopeptides; D000077427:Lipoglycopeptides; D009587:Nitrogen Isotopes; D010457:Peptidoglycan; C100708:oritavancin; D014640:Vancomycin