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Molecular interactions of a semisynthetic glycopeptide antibiotic with D-alanyl-D-alanine and D-alanyl-D-lactate residues.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 1997 Jan; Vol. 41 (1), pp. 66-71. - Publication Year :
- 1997
-
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.
- Subjects :
- Anti-Bacterial Agents chemistry
Binding, Competitive
Carboxypeptidases antagonists & inhibitors
Drug Resistance, Microbial
Peptidoglycan biosynthesis
Peptidoglycan drug effects
Protein Binding
Streptococcaceae drug effects
Streptococcaceae metabolism
Substrate Specificity
Uridine Diphosphate N-Acetylmuramic Acid analogs & derivatives
Uridine Diphosphate N-Acetylmuramic Acid metabolism
Vancomycin analogs & derivatives
Vancomycin chemistry
Vancomycin pharmacology
Anti-Bacterial Agents pharmacology
Peptidoglycan chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0066-4804
- Volume :
- 41
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 8980756
- Full Text :
- https://doi.org/10.1128/AAC.41.1.66