Inhibition of Mycobacterium tuberculosis AhpD, an element of the peroxiredoxin defense against oxidative stress.

Abstract:

: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.

authors

Koshkin A,Zhou XT,Kraus CN,Brenner JM,Bandyopadhyay P,Kuntz ID,Barry CE 3rd,Ortiz de Montellano PR

doi

10.1128/AAC.48.7.2424-2430.2004

subject

Has Abstract

pub_date

2004-07-01 00:00:00

pages

2424-30

issue

7

eissn

0066-4804

issn

1098-6596

pii

48/7/2424

journal_volume

48

pub_type

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