Affiliations: Laboratory of Tuberculosis and Research Biology, PathoGenesis Corporation, 201 Elliott Avenue West, Seattle, WA 98119, USA | Tuberculosis Research Unit, Laboratory of Intracellular Parasites, National Institutes for Allergy and Infectious Diseases, Rocky Mountain Laboratories, Hamilton, MT 59840, USA
Note: [] To whom correspondence should be addressed.
Note: [] These authors contributed equally to this work.
Abstract: The Mycobacterium tuberculosis AhpC is similar to a family of bacterial and eukaryotic antioxidant proteins with alkylhydroperoxidase (Ahp) and thioredoxin‐dependent peroxidase (TPx) activities. AhpC expression is associated with resistance to the front‐line antitubercular drug isoniazid in the naturally resistant organisms E. coli and M. smegmatis. We identified several isoniazid‐resistant M. tuberculosis isolates with ahpC promoter mutations resulting in AhpC overexpression. These strains were more resistant to cumene hydroperoxide than were wild‐type strains. However, these strains were unchanged in their sensitivity to isoniazid, refuting a role for AhpC in detoxification of this drug. All the isoniazid‐resistant, AhpC‐overexpressing strains were also deficient in activity of the mycobacterial catalase‐peroxidase KatG. KatG, the only known catalase in M. tuberculosis, is required for activation of isoniazid. We propose that compensatory ahpC promoter mutations are selected from KatG‐deficient, isoniazid‐resistant M. tuberculosis during infections, to mitigate the added burden imposed by organic peroxides on these strains.
Journal: Biofactors, vol. 10, no. 2-3, pp. 211-217, 1999
