Folate pathway disruption leads to critical disruption of methionine derivatives in Mycobacterium tuberculosis

Chem Biol. 2014 Jul 17;21(7):819-30. doi: 10.1016/j.chembiol.2014.04.009. Epub 2014 Jun 19.

Abstract

In this study, we identified antifolates with potent, targeted activity against whole-cell Mycobacterium tuberculosis (MTB). Liquid chromatography-mass spectrometry analysis of antifolate-treated cultures revealed metabolic disruption, including decreased pools of methionine and S-adenosylmethionine. Transcriptomic analysis highlighted altered regulation of genes involved in the biosynthesis and utilization of these two compounds. Supplementation with amino acids or S-adenosylmethionine was sufficient to rescue cultures from antifolate treatment. Instead of the "thymineless death" that characterizes folate pathway inhibition in a wide variety of organisms, these data suggest that MTB is vulnerable to a critical disruption of the reactions centered around S-adenosylmethionione, the activated methyl cycle.

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Dihydropteroate Synthase / antagonists & inhibitors
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Folic Acid / metabolism*
  • Folic Acid Antagonists / pharmacology*
  • Gene Expression Regulation, Bacterial / drug effects
  • Humans
  • Methionine / analogs & derivatives*
  • Methionine / metabolism*
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / metabolism*
  • S-Adenosylmethionine / metabolism
  • Species Specificity
  • Tetrahydrofolate Dehydrogenase / metabolism
  • Triazines / pharmacology

Substances

  • Antitubercular Agents
  • Folic Acid Antagonists
  • Triazines
  • BRL 6231
  • S-Adenosylmethionine
  • Folic Acid
  • Methionine
  • Tetrahydrofolate Dehydrogenase
  • Dihydropteroate Synthase