AhpC, oxidative stress and drug resistance in Mycobacterium tuberculosis

Biofactors. 1999;10(2-3):211-7. doi: 10.1002/biof.5520100219.

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.

Publication types

  • Review

MeSH terms

  • Amino Acid Sequence
  • Antioxidants / metabolism
  • Antitubercular Agents / pharmacology*
  • Drug Resistance, Microbial
  • Isoniazid / pharmacology
  • Molecular Sequence Data
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology*
  • Mycobacterium tuberculosis / genetics
  • Oxidative Stress*
  • Peroxidases / chemistry
  • Peroxidases / genetics*
  • Peroxidases / metabolism*
  • Peroxiredoxins
  • Promoter Regions, Genetic
  • Sequence Alignment
  • Sequence Homology, Amino Acid

Substances

  • Antioxidants
  • Antitubercular Agents
  • Peroxidases
  • Peroxiredoxins
  • Isoniazid