Inhibition of peptidoglycan biosynthesis in vancomycin-susceptible and -resistant bacteria by a semisynthetic glycopeptide antibiotic

Author:

Allen N E1,Hobbs J N1,Nicas T I1

Affiliation:

1. Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nea@lilly.com

Abstract

LY191145 is a p-chlorobenzyl derivative of LY264826 (A82846B) with activity against both vancomycin-susceptible and -resistant enterococci. Incorporation of L-[14C]lysine into peptidoglycan of intact vancomycin-susceptible and -resistant Enterococcus faecium was inhibited by LY191145 (50% inhibitory concentrations of 1 and 5 microgram/ml, respectively). Inhibition was accompanied by accumulation of UDP-muramyl-peptide precursors in the cytoplasm. This agent inhibited late-stage steps in peptidoglycan biosynthesis in permeabilized E. faecium when either the UDP-muramyl-pentapeptide precursor from vancomycin-susceptible E. faecium or the UDP-muramyl-pentadepsipeptide precursor from vancomycin-resistant E. faecium was used as a substrate. Inhibition of late-stage steps led to accumulation of an N-acetyl-[14C]glucosamine-labeled lipid intermediate indicative of inhibition of the transglycosylation step. Inhibition of peptidoglycan polymerization without affecting cross-linking in a particulate membrane-plus-wall-fragment assay from Aerococcus viridans was consistent with this explanation. The fact that inhibition of peptidoglycan biosynthesis by LY191145 was not readily antagonized by an excess of free acyl-D-alanyl-D-alanine or acyl-D-alanyl-D-lactate ligands indicates that the manner in which this compound inhibits transglycosylation may not be identical to that of vancomycin.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference46 articles.

1. Inhibition of peptidoglycan biosynthesis in gram-positive bacteria by LY146032;Allen N. E.;Antimicrob. Agents Chemother.,1987

2. Biosynthesis of modified peptidoglycan precursors by vancomycin-resistant Enterococcus faecium;Allen N. E.;FEMS Microbiol. Lett.,1992

3. Allen N. E. D. L. LeTourneau and J. N. Hobbs Jr. Molecular interactions of a semisynthetic glycopeptide antibiotic with D-Ala-D-Ala and D-Ala-D-Lac ligands. Submitted for publication.

4. Lipid-phosphoacetylmuramyl-pentapeptide and lipid-phosphodisaccharidepentapeptide: presumed membrane transport intermediates in cell wall synthesis;Anderson J. S.;Proc. Natl. Acad. Sci. USA,1965

5. Biosynthesis of the peptidoglycan of bacterial cell walls. II. Phospholipid carriers in the reaction sequence;Anderson J. S.;J. Biol. Chem.,1967

Cited by 55 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3