2006
DOI: 10.1128/aac.50.1.230-236.2006
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Utility of Muropeptide Ligase for Identification of Inhibitors of the Cell Wall Biosynthesis Enzyme MurF

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-␥-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… Show more

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Cited by 30 publications
(25 citation statements)
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“…Changing A 2 pm to L-Lys did not eliminate the activity with tri-to pentapeptides but resulted in significant decrease in the catalytic efficiency ( Table 2). The ability of the Mpl enzyme to add Lys-containing tri-, tetra-, and pentapeptides to UDP-MurNAc has been reported previously and was used to generate the corresponding UDP-MurNAcpeptides (2).…”
Section: Resultsmentioning
confidence: 99%
“…Changing A 2 pm to L-Lys did not eliminate the activity with tri-to pentapeptides but resulted in significant decrease in the catalytic efficiency ( Table 2). The ability of the Mpl enzyme to add Lys-containing tri-, tetra-, and pentapeptides to UDP-MurNAc has been reported previously and was used to generate the corresponding UDP-MurNAcpeptides (2).…”
Section: Resultsmentioning
confidence: 99%
“…Phosphinate transition-state analogs of the MurC to -F enzymes were synthesized by various groups in the 1990s, and some of these showed potent enzyme inhibition (at low nanomolar levels for some, illustrating druggability of the targets) but no antibacterial activity, presumably due to a lack of cell entry (127,254,310,362,403). A number of inhibitors of MurB, -C, -D, and -F, found via screens for enzyme inhibition or binding, had micromolar (in some cases, low micromolar) 50% inhibitory concentrations (IC 50 s) and no (or weak in one case [370]) antibacterial activity (11,30,103,141,364,370).…”
Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning
confidence: 99%
“…Mpl was shown to utilize tripeptide, tetrapeptide, and pentapeptide with similar efficiencies (46). Mpl also accepts peptides containing lysine in place of Dap (5). During entry into stationary phase, the expression level of Mpl increases under the control of sigma S (114).…”
Section: Mpl: Udp-n-acetylmuramate:l-alanyl-␥-d-glutamylmeso-diaminopmentioning
confidence: 99%