PMID:16377691
| Citation |
Baum, EZ, Crespo-Carbone, SM, Abbanat, D, Foleno, B, Maden, A, Goldschmidt, R and Bush, K (2006) Utility of muropeptide ligase for identification of inhibitors of the cell wall biosynthesis enzyme MurF. Antimicrob. Agents Chemother. 50:230-6 |
|---|---|
| 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. |
| Links |
PubMed PMC1346814 Online version:10.1128/AAC.50.1.230-236.2006 |
| Keywords |
Cell Wall/metabolism; Enzyme Inhibitors/isolation & purification; Enzyme Inhibitors/pharmacology; Escherichia coli/chemistry; Escherichia coli/enzymology; Peptide Synthases/antagonists & inhibitors; Peptide Synthases/metabolism; Peptidoglycan/biosynthesis |
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