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Utility of muropeptide ligase for identification of inhibitors of the cell wall biosynthesis enzyme MurF. | LitMetric

Utility of muropeptide ligase for identification of inhibitors of the cell wall biosynthesis enzyme MurF.

Antimicrob Agents Chemother

Johnson & Johnson Pharmaceutical Research & Development, LLC, 1000 Route 202, Raritan, New Jersey 08869, USA.

Published: January 2006

AI Article Synopsis

Article Abstract

MurF is a key enzyme in the biosynthesis of the bacterial cell wall in both gram-positive and gram-negative bacteria. This enzyme has not been extensively exploited as a drug target, possibly due to the difficulty in obtaining one of the substrates, UDP-MurNAc-L-Ala-gamma-D-Glu-meso-diaminopimelate, which is usually purified from bacteria. We have identified putative inhibitors of Escherichia coli MurF by a binding assay, thus bypassing the need for substrate. Inhibition of enzymatic activity was demonstrated in a high-performance liquid chromatography-based secondary assay with UDP-MurNAc-L-Ala-gamma-D-Glu-diaminopimelate substrate prepared in a novel way by using muropeptide ligase enzyme to add UDP-MurNAc to synthetic L-Ala-gamma-D-Glu-diaminopimelate; the substrate specificity of muropeptide ligase for peptides containing L-Lys in place of diaminopimelate was also investigated. Using the muropeptide ligase-generated MurF substrate, a thiazolylaminopyrimidine series of MurF enzyme inhibitors with 50% inhibitory concentration values as low as 2.5 microM was identified.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1346814PMC
http://dx.doi.org/10.1128/AAC.50.1.230-236.2006DOI Listing

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