Folate pathway disruption leads to critical disruption of methionine derivatives in Mycobacterium tuberculosis.
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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.
Nixon, M. R., Saionz, K. W., Koo, M., Szymonifka, M. J., Jung, H., Roberts, J. P., ... Sherman, D. R.
complete list of authors
Nixon, Molly R||Saionz, Kurt W||Koo, Mi-Sun||Szymonifka, Michael J||Jung, Hunmin||Roberts, Justin P||Nandakumar, Madhumita||Kumar, Anuradha||Liao, Reiling||Rustad, Tige||Sacchettini, James C||Rhee, Kyu Y||Freundlich, Joel S||Sherman, David R