Oritavancin exhibits dual mode of action to inhibit cell-wall biosynthesis in Staphylococcus aureus |
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Authors: | Kim Sung Joon Cegelski Lynette Stueber Dirk Singh Manmilan Dietrich Evelyne Tanaka Kelly S E Parr Thomas R Far Adel Rafai Schaefer Jacob |
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Affiliation: | 1 Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130, USA 2 Targanta Therapeutics, Inc., 7170 Frederick Banting, Saint Laurent, Quebec, Canada H4S 2A1 |
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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. |
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Keywords: | CPMAS, cross-polarization magic-angle spinning lipid II, N-acetylglucosamine-N-acetyl-muramyl-pentapeptide-pyrophosphoryl-undecaprenol MIC, minimum inhibitory concentration REDOR, rotational-echo double resonance VRSA, vancomycin-resistant Staphylococcus aureus LC-MS, liquid chromatography-mass spectrometry TFA, trifluoroacetic acid |
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