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Journal Article

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

N E Allen, J N Hobbs, Jr, T I Nicas
N E Allen
Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nea@lilly.com
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J N Hobbs
Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nea@lilly.com
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T I Nicas
Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nea@lilly.com
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DOI: 10.1128/AAC.40.10.2356
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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.

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Inhibition of peptidoglycan biosynthesis in vancomycin-susceptible and -resistant bacteria by a semisynthetic glycopeptide antibiotic.
N E Allen, J N Hobbs Jr, T I Nicas
Antimicrobial Agents and Chemotherapy Oct 1996, 40 (10) 2356-2362; DOI: 10.1128/AAC.40.10.2356

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Inhibition of peptidoglycan biosynthesis in vancomycin-susceptible and -resistant bacteria by a semisynthetic glycopeptide antibiotic.
N E Allen, J N Hobbs Jr, T I Nicas
Antimicrobial Agents and Chemotherapy Oct 1996, 40 (10) 2356-2362; DOI: 10.1128/AAC.40.10.2356
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