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AhpC, oxidative stress and drug resistance in Mycobacterium tuberculosis
Author(s) -
Sherman David R.,
Mdluli Khisimuzi,
Hickey Mark J.,
Barry, III Clifton E.,
Kendall Stover C.
Publication year - 1999
Publication title -
biofactors
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.204
H-Index - 94
eISSN - 1872-8081
pISSN - 0951-6433
DOI - 10.1002/biof.5520100219
Subject(s) - isoniazid , cumene hydroperoxide , mycobacterium tuberculosis , microbiology and biotechnology , mycobacterium smegmatis , catalase , drug resistance , peroxidase , tuberculosis , oxidative stress , chemistry , antimycobacterial , biology , enzyme , biochemistry , medicine , pathology , catalysis
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 ahp C 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 ahp C 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.