A silent mutation in mabA confers isoniazid resistance on Mycobacterium tuberculosis

Mol Microbiol. 2014 Feb;91(3):538-47. doi: 10.1111/mmi.12476. Epub 2014 Jan 9.


Drug resistance in Mycobacterium tuberculosis (Mtb) is caused by mutations in restricted regions of the genome. Mutations in katG, the promoter region of the mabA-inhA operon, and inhA are those most frequently responsible for isoniazid (INH) resistance. Several INH-resistant (INH(r) ) Mtb clinical isolates without mutations in these regions have been described, however, indicating that there are as yet undetermined mechanisms of INH resistance. We identified the mabA(g609a) silent mutation in a significant number of INH(r) Mtb clinical isolates without known INH resistance mutations. A laboratory strain, H37Rv, constructed with mabA(g609a) , was resistant to INH. We show here that the mabA(g609a) mutation resulted in the upregulation of inhA, a gene encoding a target for INH, converting the region adjacent to the mutation into an alternative promoter for inhA. The mabA(g609a) silent mutation results in a novel mechanism of INH resistance, filling in a missing piece of INH resistance in Mtb.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / biosynthesis
  • Bacterial Proteins / genetics*
  • Drug Resistance, Bacterial*
  • Gene Expression
  • Humans
  • Isoniazid / pharmacology*
  • Molecular Sequence Data
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics
  • Oxidoreductases / biosynthesis
  • Point Mutation*
  • Promoter Regions, Genetic
  • Sequence Analysis, DNA
  • Tuberculosis / microbiology
  • Up-Regulation


  • Antitubercular Agents
  • Bacterial Proteins
  • Oxidoreductases
  • InhA protein, Mycobacterium
  • Isoniazid

Associated data

  • GENBANK/AL123456