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.
author list (cited authors)
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