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Antimicrobial Agents and Chemotherapy, June 2002, p. 1793-1799, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1793-1799.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antibacterial Activities and Characterization of Novel Inhibitors of LpxC

John M. Clements,* Fanny Coignard, Ian Johnson, Stephen Chandler, Shilpa Palan, Andrew Waller, Jac Wijkmans, and Michael G. Hunter

British Biotech Pharmaceuticals Ltd., Oxford OX4 6LY, United Kingdom

Received 8 October 2001/ Returned for modification 14 January 2002/ Accepted 12 March 2002

Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of gram-negative bacteria. Lipid A is required for bacterial growth and virulence, and inhibition of its biosynthesis is lethal to bacteria. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a metalloenzyme that catalyzes the second step in the biosynthesis of lipid A. Inhibitors of LpxC have previously been shown to have antibiotic activities. We have screened a metalloenzyme inhibitor library for antibacterial activities against an Escherichia coli strain with reduced LpxC activity. From this screen, a series of sulfonamide derivatives of the {alpha}-(R)-amino hydroxamic acids, exemplified by BB-78484 and BB-78485, have been identified as having potent inhibitory activities against LpxC in an in vitro assay. Leads from this series showed gram-negative selective activities against members of the Enterobacteriaceae, Serratia marcescens, Morganella morganii, Haemophilus influenzae, Moraxella catarrhalis, and Burkholderia cepacia. BB-78484 was bactericidal against E. coli, achieving 3-log killing in 4 h at a concentration 4 times above the MIC, as would be predicted for an inhibitor of lipid A biosynthesis. E. coli mutants with decreased susceptibility to BB-78484 were selected. Analysis of these mutants revealed that resistance arose as a consequence of mutations in the fabZ or lpxC genes. These data confirm the antibacterial target of BB-78484 and BB-78485 and validate LpxC as a target for gram-negative selective antibacterials.

* Corresponding author. Mailing address: British Biotech Pharmaceuticals Ltd., Watlington Rd., Oxford OX4 6LY, United Kingdom. Phone: 44 1865 748747. Fax: 44 1865 781034. E-mail: clements{at}britbio.co.uk.

Antimicrobial Agents and Chemotherapy, June 2002, p. 1793-1799, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1793-1799.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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