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Inhibition of Mycobacterium tuberculosis AhpD, an Element of the Peroxiredoxin Defense against Oxidative Stress. Aleksey Koshkin, 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 Ki 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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