AAC Accepts, published online ahead of print on 1 October 2007

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00845-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A MurF inhibitor that disrupts cell wall biosynthesis in Escherichia coli

Ellen Z. Baum^*, Steven M. Crespo-Carbone, Alexandra Klinger, Barbara D. Foleno, Ignatius Turchi, Mark Macielag, and Karen Bush

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, New Jersey 08869

^* To whom correspondence should be addressed. Email: ebaum{at}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 was identified which bound to the E. coli enzyme and inhibited its activity. To derive additional chemotypes lacking the 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 derivative (4-PP) identified by this process displayed antibacterial activity (MIC of 8 µg/ml against permeable E. coli) including cell lysis and a 5 log₁₀ 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.

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