Vancomycin derivative with damaged D-Ala-D-Ala binding cleft binds to cross-linked peptidoglycan in the cell wall of Staphylococcus aureus.
Des-N-methylleucyl-4-(4-fluorophenyl)benzyl-vancomycin (DFPBV) retains activity against vancomycin-resistant pathogens despite its damaged d-Ala-d-Ala binding cleft. Using solid-state nuclear magnetic resonance (NMR), a DFPBV binding site in the cell walls of whole cells of Staphylococcus aureus has been identified. The cell walls were labeled with d-[1-(13)C]alanine, [1-(13)C]glycine, and l-[epsilon-(15)N]lysine. Internuclear distances from (19)F of the DFPBV to the (13)C and (15)N labels of the cell-wall peptidoglycan were determined by rotational-echo double-resonance (REDOR) NMR. The (13)C{(19)F} and (15)N{(19)F} REDOR spectra show that, in situ, DFPBV binds to the peptidoglycan as a monomer with its vancosamine hydrophobic side chain positioned near a pentaglycyl bridge. This result suggests that the antimicrobial activity of other vancosamine-modified glycopeptides depends upon both d-Ala-d-Ala stem-terminus recognition (primary binding site) and stem-bridge recognition (secondary binding site).
Kim
Sung Joon
SJ
Department of Chemistry, Washington University, St. Louis, Missouri 63130, USA.
Matsuoka
Shigeru
S
Patti
Gary J
GJ
Schaefer
Jacob
J
D001665:Binding Sites; D002473:Cell Wall / Q000378:metabolism*; D003432:Cross-Linking Reagents; D004151:Dipeptides / Q000737:chemistry*; D008968:Molecular Conformation; D010457:Peptidoglycan / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000378:metabolism*; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism
D003432:Cross-Linking Reagents; D004151:Dipeptides; D010457:Peptidoglycan; C529116:des-N-methylleucyl-4-(4-fluorophenyl)benzylvancomycin; C002956:alanylalanine; D014640:Vancomycin