Metabolic regulation of mycobacterial growth and antibiotic sensitivity

PLoS Biol. 2011 May;9(5):e1001065. doi: 10.1371/journal.pbio.1001065. Epub 2011 May 24.


Treatment of chronic bacterial infections, such as tuberculosis (TB), requires a remarkably long course of therapy, despite the availability of drugs that are rapidly bacteriocidal in vitro. This observation has long been attributed to the presence of bacterial populations in the host that are "drug-tolerant" because of their slow replication and low rate of metabolism. However, both the physiologic state of these hypothetical drug-tolerant populations and the bacterial pathways that regulate growth and metabolism in vivo remain obscure. Here we demonstrate that diverse growth-limiting stresses trigger a common signal transduction pathway in Mycobacterium tuberculosis that leads to the induction of triglyceride synthesis. This pathway plays a causal role in reducing growth and antibiotic efficacy by redirecting cellular carbon fluxes away from the tricarboxylic acid cycle. Mutants in which this metabolic switch is disrupted are unable to arrest their growth in response to stress and remain sensitive to antibiotics during infection. Thus, this regulatory pathway contributes to antibiotic tolerance in vivo, and its modulation may represent a novel strategy for accelerating TB treatment.

Publication types

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

MeSH terms

  • Acetyl Coenzyme A / metabolism
  • Anaerobiosis
  • Animals
  • Antitubercular Agents / pharmacology*
  • Bacterial Load
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Biosynthetic Pathways
  • Citric Acid Cycle
  • Drug Resistance, Bacterial / genetics*
  • Ethambutol / pharmacology
  • Isoniazid / pharmacology
  • Lung / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / physiology
  • Pyrazinamide / pharmacology
  • Spleen / microbiology
  • Stress, Physiological
  • Triglycerides / metabolism
  • Tuberculosis, Pulmonary / microbiology


  • Antitubercular Agents
  • Bacterial Proteins
  • Triglycerides
  • Pyrazinamide
  • Acetyl Coenzyme A
  • Ethambutol
  • Isoniazid