Isocitrate Lyase Mediates Broad Antibiotic Tolerance in Mycobacterium Tuberculosis

Nat Commun. 2014 Jun 30;5:4306. doi: 10.1038/ncomms5306.

Abstract

Mycobacterium tuberculosis (Mtb) is a persistent intracellular pathogen intrinsically tolerant to most antibiotics. However, the specific factors that mediate this tolerance remain incompletely defined. Here we apply metabolomic profiling to discover a common set of metabolic changes associated with the activities of three clinically used tuberculosis drugs, isoniazid, rifampicin and streptomycin. Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant. These results identify a previously undescribed role for Mtb's ICLs in antioxidant defense as a mechanism of antibiotic tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / metabolism
  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Citric Acid Cycle
  • Drug Resistance, Bacterial
  • Isocitrate Lyase / genetics
  • Isocitrate Lyase / metabolism*
  • Microbial Viability
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / metabolism

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Isocitrate Lyase