@article{4e23f60042c3434e8f1ea1e79f72340e,
title = "Folate pathway disruption leads to critical disruption of methionine derivatives in mycobacterium tuberculosis",
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.",
author = "Nixon, {Molly R.} and Saionz, {Kurt W.} and Koo, {Mi Sun} and Szymonifka, {Michael J.} and Hunmin Jung and Roberts, {Justin P.} and Madhumita Nandakumar and Anuradha Kumar and Reiling Liao and Tige Rustad and Sacchettini, {James C.} and Rhee, {Kyu Y.} and Freundlich, {Joel S.} and Sherman, {David R.}",
note = "Funding Information: D.R.S. acknowledges support from the Paul G. Allen Family Foundation and NIH (U19 AI106761, and training grant T32AI055396 in bacterial pathogenesis awarded to M.R.N.). J.S.F. acknowledges funding from UMDNJ–NJMS and the Foundation of UMDNJ. K.Y.R. acknowledges funding from a Burroughs Wellcome Career Award in the Biomedical Sciences and the Bill and Melinda Gates TB Drug Accelerator Program (OPP1024050). J.C.S. acknowledges support from the Welch Foundation (grant A-0015). We thank Jacobus Pharmaceuticals for the gift of WR99210 compound, Sebastien Gagnieux for access to clinical strains of MTB, Kyle Minch for help with figures, and members of the Sherman Lab for technical assistance and valuable advice. ",
year = "2014",
month = jul,
day = "17",
doi = "10.1016/j.chembiol.2014.04.009",
language = "English (US)",
volume = "21",
pages = "819--830",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "7",
}