PMID:12019092
| Citation |
Clements, JM, Coignard, F, Johnson, I, Chandler, S, Palan, S, Waller, A, Wijkmans, J and Hunter, MG (2002) Antibacterial activities and characterization of novel inhibitors of LpxC. Antimicrob. Agents Chemother. 46:1793-9 |
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| Abstract |
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. |
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| Keywords |
Amidohydrolases/antagonists & inhibitors; Amidohydrolases/genetics; Anti-Bacterial Agents/pharmacology; Bacteria/drug effects; Bacteria/enzymology; Bacteria/genetics; DNA, Recombinant/genetics; Drug Resistance, Microbial; Drug Synergism; Enzyme Inhibitors/pharmacology; Escherichia coli/genetics; Genotype; Hydro-Lyases/genetics; Microbial Sensitivity Tests; Mutation/genetics; Naphthalenes/pharmacology; Plasmids/genetics; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides/pharmacology; Time Factors |
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