title: Desleucyl-Oritavancin with a Damaged d-Ala-d-Ala Binding Site Inhibits the Transpeptidation Step of Cell-Wall Biosynthesis in Whole Cells of Staphylococcus aureus.
abstract: We have used solid-state nuclear magnetic resonance to characterize the exact nature of the dual mode of action of oritavancin in preventing cell-wall assembly in Staphylococcus aureus. Measurements performed on whole cells labeled selectively in vivo have established that des-N-methylleucyl-N-4-(4-fluorophenyl)benzyl-chloroeremomycin, an Edman degradation product of [19F]oritavancin, which has a damaged d-Ala-d-Ala binding aglycon, is a potent inhibitor of the transpeptidase activity of cell-wall biosynthesis. The desleucyl drug binds to partially cross-linked peptidoglycan by a cleft formed between the drug aglycon and its biphenyl hydrophobic side chain. This type of binding site is present in other oritavancin-like glycopeptides, which suggests that for these drugs a similar transpeptidase inhibition occurs.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University , 101 Bagby Avenue, Waco, Texas 76798, United States.
authors.forename: Sung Joon
authors.identifier: 0000-0002-2007-6606
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Washington University , One Brookings Drive, St. Louis, Missouri 63130, United States.
authors.forename: Manmilan
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Chemistry, Washington University , One Brookings Drive, St. Louis, Missouri 63130, United States.
authors.forename: Shasad
authors.initials: S
authors.lastname: Sharif
authors.affiliation: Department of Chemistry, Washington University , One Brookings Drive, St. Louis, Missouri 63130, United States.
authors.forename: Jacob
authors.identifier: 0000-0002-7544-6408
authors.initials: J
authors.lastname: Schaefer
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002473:Cell Wall / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry / Q000378:metabolism; D006020:Glycopeptides / Q000737:chemistry / Q000494:pharmacology*; D007554:Isotopes; D000077427:Lipoglycopeptides; D010457:Peptidoglycan / Q000737:chemistry / Q000378:metabolism; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D014640:Vancomycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004151:Dipeptides; D006020:Glycopeptides; D007554:Isotopes; D000077427:Lipoglycopeptides; D010457:Peptidoglycan; C112142:chloroeremomycin; D005461:Fluorine; C002956:alanylalanine; D014640:Vancomycin; D010458:Peptidyl Transferases; C100708:oritavancin