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Metabolic reconstruction reveals ATP salvage as a key response to trimethoprim treatment

Cailean Carter1,2,3, Dipali Singh1,3, John Wain1,2,3

  • 1Microbes and Food Safety, Quadram Institute Bioscience, Norwich NR4 7UQ, UK.

Iscience
|April 20, 2026
PubMed

Insights

Trimethoprim antibiotic efficacy varies with growth media. In low-purine conditions, it triggers ATP salvage for DNA repair in Escherichia coli, impacting treatment outcomes.

Area of Science:

  • Microbiology
  • Metabolic Engineering
  • Pharmacology

Background:

  • Trimethoprim is crucial for treating urinary tract infections.
  • Its precise killing mechanism is unclear due to complex metabolic effects.
  • Growth media composition can alter trimethoprim's effectiveness.

Purpose of the Study:

  • To elucidate trimethoprim's metabolic impact on Escherichia coli.
  • To investigate how nutrient availability modifies trimethoprim outcomes.
  • To explore personalized medicine strategies based on media composition.

Main Methods:

  • Utilized flux balance analysis on a genome-scale metabolic model of E. coli.
  • Simulated trimethoprim activity under bacteriostatic and bactericidal conditions.
  • Experimentally validated findings using ATP bioluminescence assays on clinical isolates.

Main Results:

  • Trimethoprim induces ATP salvage for DNA repair when environmental purines/nucleosides are scarce.
  • Growth media significantly influences trimethoprim's bacteriostatic/bactericidal effects.
  • Identified a key metabolic vulnerability of E. coli to trimethoprim.

Conclusions:

  • Media composition is a critical factor in trimethoprim efficacy.
  • Understanding metabolic context enables prediction of trimethoprim response.
  • Findings support personalized antibiotic therapy approaches.
Keywords:
biochemistrymetabolomicsmicrobiology

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