AhpC, oxidative stress and drug resistance in Mycobacterium tuberculosis.
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.
Sherman
D R
DR
Laboratory of Tuberculosis and Research Biology, PathoGenesis Corporation, Seattle, WA 98119, USA.
Mdluli
K
K
Hickey
M J
MJ
Barry
C E
CE
Stover
C K
CK
D000595:Amino Acid Sequence; D000975:Antioxidants / Q000378:metabolism; D000995:Antitubercular Agents / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D007538:Isoniazid / Q000494:pharmacology; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D018384:Oxidative Stress; D010544:Peroxidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D054464:Peroxiredoxins; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000975:Antioxidants; D000995:Antitubercular Agents; D010544:Peroxidases; D054464:Peroxiredoxins; D007538:Isoniazid