Isoniazid resistance without a loss of fitness in Mycobacterium tuberculosis

Nat Commun. 2012 Mar 20;3:753. doi: 10.1038/ncomms1724.

Abstract

The emergence of multi- and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) has intensified the critical public health implications of this global disease. The fitness of Mycobacterium tuberculosis (M.tb.) strains exhibiting MDR and XDR phenotypes is of fundamental importance in predicting whether the MDR-/XDR-TB epidemic will be sustained across the human population. Here we describe a potential mechanism of M.tb. resistance to the TB drug isoniazid (INH) conferred by loss of a sigma factor, SigI. We demonstrate that the gain of INH resistance in the M.tb. ΔsigI mutant might not diminish the organism's fitness for causing disease. These findings have significant implications when considering the ability of drug-resistant M.tb. strains to initiate untreatable TB epidemics, as it is possible that loss or alteration of SigI function could have a role in the generation of MDR and XDR M.tb. strains of suitable fitness to spread in a community setting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / biosynthesis
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Catalase / biosynthesis
  • Catalase / genetics
  • Drug Resistance, Multiple, Bacterial
  • Genes, Bacterial
  • Genes, Regulator
  • Isoniazid / pharmacology*
  • Macrophages / immunology
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred BALB C
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / metabolism
  • Mycobacterium tuberculosis / pathogenicity
  • Regulon
  • Sigma Factor / genetics*
  • Transcription, Genetic
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology
  • Tuberculosis, Multidrug-Resistant / microbiology*

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Sigma Factor
  • Catalase
  • katG protein, Mycobacterium tuberculosis
  • Isoniazid