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Papers In Press, published online ahead of print February 26, 2003
Biochemistry & Biophysics, Texas A&M University, College Station, TX 77843
Corresponding Author: mack{at}usa.net
Tuberculosis and malaria together result in an estimated 5 million deaths annually. The spread of multi-drug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties. While genetically unrelated, both organisms use a type II Fatty Acid Synthase (FAS-II) system for synthesis of long chain fatty acids. Enoyl acyl carrier protein reductase (ENR), a key FAS-II enzyme, has been repeatedly validated as an effective antimicrobial target. Using high throughput inhibitor screens with a combinatorial library, we have identified two novel classes of compounds with activity against the M. tuberculosis and P. falciparum enzyme (referred to as InhA and PfENR respectively). The crystal structure of InhA complexed with NAD+ and one of the inhibitors was determined to elucidate the mode of binding to this novel compound series. Structural analysis of InhA with the broad-spectrum antimicrobial triclosan revealed a unique stoichiometry where the enzyme contained either a single triclosan molecule in a configuration typical of other bacterial ENR: triclosan structures, or harbored two triclosan molecules bound to the active site of the enzyme. Significantly, these compounds do not require activation, and are effective against wild type and drug-resistant strains of M. tuberculosis and P. falciparum. Moreover, they provide broader chemical diversity and elucidate key elements of inhibitor binding to InhA for subsequent chemical optimization.
J. Biol. Chem, 10.1074/jbc.M211968200
Submitted on November 25, 2002
Revised on February 14, 2003
Accepted on February 26, 2003
Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data
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