title: Molecular interactions of a semisynthetic glycopeptide antibiotic with D-alanyl-D-alanine and D-alanyl-D-lactate residues.
abstract: LY191145 is an N-alkylated glycopeptide antibiotic (the p-chlorobenzyl derivative of LY264826) with activity against vancomycin-susceptible and -resistant bacteria. Similar to vancomycin, LY191145 inhibited polymerization of peptidoglycan when muramyl pentapeptide served as a substrate but not when muramyl tetrapeptide was used, signifying a substrate-dependent mechanism of inhibition. Examination of ligand binding affinities for LY191145 and the effects of this agent on R39 D,D-carboxypeptidase action showed that, similar to vancomycin, LY191145 had an 800-fold greater affinity for N,N'-diacetyl-L-Lys-D-Ala-D-Ala than for N,N'-diacetyl-L-Lys-D-Ala-D-Lac. The antibacterial activity of LY191145 was antagonized by N,N'-diacetyl-L-Lys-D-Ala-D-Ala, but the molar excess required for complete suppression exceeded that needed to suppress inhibition by vancomycin. LY191145 is strongly dimerized and the p-chlorobenzyl side chain facilitates interactions with bacterial membranes. These findings are consistent with a mechanism of inhibition where interactions between antibiotic and D-Ala-D-Ala or D-Ala-D-Lac residues depend on intramolecular effects occurring at the subcellular target site.
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nea@lilly.com
authors.forename: N E
authors.initials: NE
authors.lastname: Allen
authors.forename: D L
authors.initials: DL
authors.lastname: LeTourneau
authors.forename: J N
authors.initials: JN
authors.lastname: Hobbs
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors; D004352:Drug Resistance, Microbial; D010457:Peptidoglycan / Q000096:biosynthesis / Q000737:chemistry* / Q000187:drug effects; D011485:Protein Binding; D013289:Streptococcaceae / Q000187:drug effects / Q000378:metabolism; D013379:Substrate Specificity; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D014640:Vancomycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C098177:LY 191145; D010457:Peptidoglycan; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C057893:chloroorienticin A; C002225:UDP-N-acetylmuramic acid pentapeptide; D014640:Vancomycin; D002268:Carboxypeptidases