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

Molly R. Nixon, Kurt W. Saionz, Mi Sun Koo, Michael J. Szymonifka, Hunmin Jung, Justin P. Roberts, Madhumita Nandakumar, Anuradha Kumar, Reiling Liao, Tige Rustad, James C. Sacchettini, Kyu Y. Rhee, Joel S. Freundlich, David R. Sherman

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)819-830
Number of pages12
JournalChemistry and Biology
Volume21
Issue number7
DOIs
StatePublished - Jul 17 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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