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Antimicrobial Agents and Chemotherapy, July 2004, p. 2424-2430, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2424-2430.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Mycobacterium tuberculosis AhpD, an Element of the Peroxiredoxin Defense against Oxidative Stress

Department of Pharmaceutical Chemistry, University of California—San Francisco, San Francisco, California 94143-2280,¹ Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Rockville, Maryland 20852²

Received 6 January 2004/ Returned for modification 24 February 2004/ Accepted 8 March 2004

The resistance of Mycobacterium tuberculosis to isoniazid (INH) is largely linked to suppression of a catalase-peroxidase enzyme (KatG) that activates INH. In the absence of KatG, antioxidant protection is provided by enhanced expression of the peroxiredoxin AhpC, which is itself reduced by AhpD, a protein with low alkylhydroperoxidase activity of its own. Inhibition of AhpD might therefore impair the antioxidant protection afforded by AhpC and make KatG-negative strains more sensitive to oxidative stress. We report here that the 3(E),17-dioxime of testosterone is a potent competitive AhpD inhibitor, with a K_i of 50 ± 2 nM. The inhibitor is stereospecific, in that the 3(E) but not 3(Z) isomer is active. Computational studies provide support for a proposed AhpD substrate binding site. However, the inhibitor does not completely suppress the in vitro activity of AhpC/AhpD, because a low titer of AhpD suffices to maintain AhpC activity. This finding, and the low solubility of the inhibitor, explains its inability to suppress the growth of INH-resistant M. tuberculosis in infected mouse lungs.

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