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1: Antimicrob Agents Chemother. 2007 Dec;51(12):4420-6. Epub 2007 Oct 1.
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A MurF inhibitor that disrupts cell wall biosynthesis in Escherichia coli.

Baum EZ, Crespo-Carbone SM, Klinger A, Foleno BD, Turchi I, Macielag M, Bush K.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, NJ 08869, USA. ebaum@prdus.jnj.com

MurF is an essential enzyme of bacterial cell wall biosynthesis. Few MurF inhibitors have been reported, and none have displayed measurable antibacterial activity. Through the use of a MurF binding assay, a series of 8-hydroxyquinolines that bound to the Escherichia coli enzyme and inhibited its activity was identified. To derive additional chemotypes lacking 8-hydroxyquinoline, a known chelating moiety, a pharmacophore model was constructed from the series and used to select compounds for testing in the MurF binding and enzymatic inhibition assays. Whereas the original diverse library yielded 0.01% positive compounds in the binding assay, of which 6% inhibited MurF enzymatic activity, the pharmacophore-selected set yielded 14% positive compounds, of which 37% inhibited the enzyme, suggesting that the model enriched for compounds with affinity to MurF. A 4-phenylpiperidine (4-PP) derivative identified by this process displayed antibacterial activity (MIC of 8 microg/ml against permeable E. coli) including cell lysis and a 5-log(10)-unit decrease in CFU. Importantly, treatment of E. coli with 4-PP resulted in a 15-fold increase in the amount of the MurF UDP-MurNAc-tripeptide substrate, and a 50% reduction in the amount of the MurF UDP-MurNAc-pentapeptide product, consistent with inhibition of the MurF enzyme within bacterial cells. Thus, 4-PP is the first reported inhibitor of the MurF enzyme that may contribute to antibacterial activity by interfering with cell wall biosynthesis.

PMID: 17908943 [PubMed - indexed for MEDLINE]

PMCID: PMC2167990