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Antimicrobial Agents and Chemotherapy, December 2007, p. 4420-4426, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00845-07
Copyright © 2007, American Society for Microbiology. 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

Received 28 June 2007/ Returned for modification 27 August 2007/ Accepted 25 September 2007

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 µg/ml against permeable E. coli) including cell lysis and a 5-log₁₀-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.

Published ahead of print on 1 October 2007.

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Present address: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 8 Clarke Drive, Cranbury, NJ 08512.