This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Allen, N. E. Articles by Hobbs, J. N. Search for Related Content PubMed PubMed Citation Articles by Allen, N. E. Articles by Hobbs, J. N., Jr

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, Jan 1997, 66-71, Vol 41, No. 1
Copyright © 1997 by the American Society for Microbiology. All rights reserved.

Molecular interactions of a semisynthetic glycopeptide antibiotic with D-alanyl-D-alanine and D-alanyl-D-lactate residues

NE Allen, DL LeTourneau and JN Hobbs Jr
Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nea@lilly.com

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.

This article has been cited by other articles:

• Higgins, D. L., Chang, R., Debabov, D. V., Leung, J., Wu, T., Krause, K. M., Sandvik, E., Hubbard, J. M., Kaniga, K., Schmidt, D. E. Jr., Gao, Q., Cass, R. T., Karr, D. E., Benton, B. M., Humphrey, P. P. (2005). Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 49: 1127-1134 [Abstract] [Full Text]  
• Allen, N. E., LeTourneau, D. L., Hobbs, J. N. Jr., Thompson, R. C. (2002). Hexapeptide Derivatives of Glycopeptide Antibiotics: Tools for Mechanism of Action Studies. Antimicrob. Agents Chemother. 46: 2344-2348 [Abstract] [Full Text]  
• Mercier, R.-C., Stumpo, C., Rybak, M. J. (2002). Effect of growth phase and pH on the in vitro activity of a new glycopeptide, oritavancin (LY333328), against Staphylococcus aureus and Enterococcus faecium. J Antimicrob Chemother 50: 19-24 [Abstract] [Full Text]  
• Arthur, M., Depardieu, F., Reynolds, P., Courvalin, P. (1999). Moderate-Level Resistance to Glycopeptide LY333328 Mediated by Genes of the vanA and vanB Clusters in Enterococci. Antimicrob. Agents Chemother. 43: 1875-1880 [Abstract] [Full Text]  
• Ge, M., Chen, Z., Onishi, H. R., Kohler, J., Silver, L. L., Kerns, R., Fukuzawa, S., Thompson, C., Kahne, D. (1999). Vancomycin Derivatives That Inhibit Peptidoglycan Biosynthesis Without Binding D-Ala-D-Ala. Science 284: 507-511 [Abstract] [Full Text]