| Title | Folate pathway disruption leads to critical disruption of methionine derivatives in Mycobacterium tuberculosis. |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Nixon MR, Saionz KW, Koo M-S, Szymonifka MJ, Jung H, Roberts JP, Nandakumar M, Kumar A, Liao R, Rustad T, Sacchettini, James C, Rhee KY, Freundlich JS, Sherman DR |
| Journal | Chem Biol |
| Volume | 21 |
| Issue | 7 |
| Pagination | 819-30 |
| Date Published | 2014 Jul 17 |
| ISSN | 1879-1301 |
| Keywords | Antitubercular Agents, Dihydropteroate Synthase, Drug Evaluation, Preclinical, Drug Synergism, Folic Acid, Folic Acid Antagonists, Gene Expression Regulation, Bacterial, Humans, Methionine, Mycobacterium tuberculosis, S-Adenosylmethionine, Species Specificity, Tetrahydrofolate Dehydrogenase, Triazines |
| 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. |
| DOI | 10.1016/j.chembiol.2014.04.009 |
| Alternate Journal | Chem Biol |
| PubMed ID | 24954008 |