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J. Biol. Chem., Vol. 278, Issue 23, 20851-20859, June 6, 2003

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Targeting Tuberculosis and Malaria through Inhibition of Enoyl Reductase

COMPOUND ACTIVITY AND STRUCTURAL DATA^*

Mack R. Kuo , Hector R. Morbidoni  ¶, David Alland ||, Scott F. Sneddon **, Brian B. Gourlie **, Mark M. Staveski **, Marina Leonard **, Jill S. Gregory **, Andrew D. Janjigian **, Christopher Yee **, James M. Musser , Barry Kreiswirth , Hiroyuki Iwamoto , Remo Perozzo , William R. Jacobs, Jr.  ¶¶, James C. Sacchettini  |||| and David A. Fidock 

From the Department of Biochemistry and Biophysics, Texas A & M University, College Station, Texas 77843 and Department of Microbiology and Immunology and ^¶¶Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461, ^||Division of Infectious Diseases and the Center for Emerging Pathogens, New Jersey Medical School, Newark, New Jersey 07103, ^**Genzyme Drug Discovery, Genzyme Corp., Cambridge, Massachusetts 02139-1562, Laboratory of Human Bacterial Pathogenesis, Division of Intramural Research, NIAID, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana 59840, and Public Health Research Institute TB Center, New York, New York 10016

Tuberculosis and malaria together result in an estimated 5 million deaths annually. The spread of multidrug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties. Although genetically unrelated, both organisms use a type II fatty-acid synthase system. Enoyl acyl carrier protein reductase (ENR), a key type 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. 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. 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.

Received for publication, November 25, 2002 , and in revised form, February 14, 2003.

The atomic coordinates and structure factors (code 1P44 and 1P45) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by National Institutes of Health Grant AI43268 and the Robert A. Welch Foundation (to J. C. S.) and by a Burroughs Wellcome Fund New Initiatives in Malaria Research Award (to D. A. F. and W. R. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Career Investigator of the Consejo de Investigaciones de la Universidad Nacional de Rosario, Argentina.

^|||| To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics, Texas A & M University, Biochemistry and Biophysics Bldg., Rm. 221, College Station, TX 77843. E-mail: sacchett{at}tamu.edu.

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