title: Chlorobiphenyl-desleucyl-vancomycin inhibits the transglycosylation process required for peptidoglycan synthesis in bacteria in the absence of dipeptide binding.
abstract: Novel glycopeptide analogs are known that have activity on vancomycin resistant enterococci despite the fact that the primary site for drug interaction, D-ala-D-ala, is replaced with D-ala-D-lactate. The mechanism of action of these compounds may involve dimerization and/or membrane binding, thus enhancing interaction with D-ala-D-lactate, or a direct interaction with the transglycosylase enzymes involved in peptidoglycan polymerization. We evaluated the ability of vancomycin (V), desleucyl-vancomycin (desleucyl-V), chlorobiphenyl-vancomycin (CBP-V), and chlorobiphenyl-desleucyl-vancomycin (CBP-desleucyl-V) to inhibit (a) peptidoglycan synthesis in vitro using UDP-muramyl-pentapeptide and UDP-muramyl-tetrapeptide substrates and (b) growth and peptidoglycan synthesis in vancomycin resistant enterococci. Compared to V or CBP-V, CBP-desleucyl-V retained equivalent potency in these assays, whereas desleucyl-V was inactive. In addition, CBP-desleucyl-V caused accumulation of N-acetylglucosamine-beta-1, 4-MurNAc-pentapeptide-pyrophosphoryl-undecaprenol (lipid II). These data show that CBP-desleucyl-V inhibits peptidoglycan synthesis at the transglycosylation stage in the absence of binding to dipeptide.
authors.affiliation: Incara Research Laboratories, 8 Cedar Brook Drive, Cranbury, NJ 08512, USA. rgoldman@irl.incara.com
authors.forename: R C
authors.initials: RC
authors.lastname: Goldman
authors.forename: E R
authors.initials: ER
authors.lastname: Baizman
authors.forename: C B
authors.initials: CB
authors.lastname: Longley
authors.forename: A A
authors.initials: AA
authors.lastname: Branstrom
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism*; D004151:Dipeptides / Q000378:metabolism; D006031:Glycosylation; D010457:Peptidoglycan / Q000096:biosynthesis*; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004151:Dipeptides; D010457:Peptidoglycan; C405766:chlorobiphenyl-desleucyl-vancomycin; D014640:Vancomycin