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Despite the therapeutic importance of antifolates, the links between their direct antimetabolite activity and downstream consequences remain incompletely understood. Here we employ metabolomics to examine the complete metabolic effects of the antibiotic trimethoprim in E. coli. In rich media, trimethoprim treatment causes thymineless death. In minimal media, in contrast, trimethoprim addition results in rapid stoppage of cell growth and stable cell stasis. We show that initial impairment of cell growth is due to rapid depletion of glycine and associated activation of the stringent response. Long-term stasis is due to purine insufficiency. Thus, E. coli has dual systems for surviving folate depletion and avoiding thymineless death: a short-term response based on sensing of amino acids and a long-term response based on sensing of nucleotides.

Antifolate-Induced Depletion of Intracellular Glycine and Purines Inhibits Thymineless Death in E. coli