title: Folate pathway disruption leads to critical disruption of methionine derivatives in Mycobacterium tuberculosis.
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.
authors: Interdisciplinary Program in Pathobiology, Department of Global Health, University of Washington, Seattle, WA 98195, USA; Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors: Molly R
authors: MR
authors: Nixon
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors: Kurt W
authors: KW
authors: Saionz
authors: Department of Pharmacology and Physiology and Medicine, Center for Emerging and Reemerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ 07103, USA.
authors: Mi-Sun
authors: MS
authors: Koo
authors: Department of Pharmacology and Physiology and Medicine, Center for Emerging and Reemerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ 07103, USA.
authors: Michael J
authors: MJ
authors: Szymonifka
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors: Hunmin
authors: H
authors: Jung
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors: Justin P
authors: JP
authors: Roberts
authors: Departments of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors: Madhumita
authors: M
authors: Nandakumar
authors: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors: Anuradha
authors: A
authors: Kumar
authors: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors: Reiling
authors: R
authors: Liao
authors: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors: Tige
authors: T
authors: Rustad
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors: James C
authors: JC
authors: Sacchettini
authors: Departments of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors: Kyu Y
authors: KY
authors: Rhee
authors: Department of Pharmacology and Physiology and Medicine, Center for Emerging and Reemerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ 07103, USA.
authors: Joel S
authors: JS
authors: Freundlich
authors: Interdisciplinary Program in Pathobiology, Department of Global Health, University of Washington, Seattle, WA 98195, USA; Seattle Biomedical Research Institute, Seattle, WA 98109, USA. Electronic address: david.sherman@seattlebiomed.org.
authors: David R
authors: DR
authors: Sherman
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005492:Folic Acid / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism; D013045:Species Specificity; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D005493:Folic Acid Antagonists; D014227:Triazines; C006201:BRL 6231; D012436:S-Adenosylmethionine; D005492:Folic Acid; D008715:Methionine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase