Molecular basis for the exquisite sensitivity of Mycobacterium tuberculosis to isoniazid

Y. Zhang, S. Dhandayuthapani, V. Deretic

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

The exceptional sensitivity of Mycobacterium tuberculosis to isonicotinic acid hydrazide (INH) lacks satisfactory definition. M. tuberculosis is a natural mutant in oxyR, a central regulator of peroxide stress response. The ahpC gene, which encodes a critical subunit of alkyl hydroperoxide reductase, is one of the targets usually controlled by oxyR in bacteria. Unlike in mycobacterial species less susceptible to INH, the expression of ahpC was below detection limits at the protein level in INH- sensitive M. tuberculosis and Mycobacterium boris strains. In contrast, AhpC was detected in several series of isogenic INH-resistant (INH(r)) derivatives. In a demonstration of the critical role of ahpC in sensitivity to INH, insertional inactivation of ahpC on the chromosome of Mycobacterium smegmatis, a species naturally insensitive to INH, dramatically increased its susceptibility to this compound. These findings suggest that AhpC counteracts the action of INH and that the levels of its expression may govern the intrinsic susceptibility of mycobacteria to this front-line antituberculosis drug.

Original languageEnglish (US)
Pages (from-to)13212-13216
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number23
DOIs
StatePublished - Nov 12 1996

Keywords

  • ahpC
  • gene replacements
  • mycobacteria
  • oxidative stress
  • oxyR

ASJC Scopus subject areas

  • General

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