Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs

Marissa B. Guzzo, Hoa T. Nguyen, Thanh H. Pham, Monika Wyszczelska-Rokiel, Hieronim Jakubowski, Kerstin A. Wolff, Sam Ogwang, Joseph L. Timpona, Soumya Gogula, Michael R. Jacobs, Markus Ruetz, Bernhard Kräutler, Donald W. Jacobsen, Guo Fang Zhang, Liem Nguyen

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


The methylfolate trap, a metabolic blockage associated with anemia, neural tube defects, Alzheimer’s dementia, cardiovascular diseases, and cancer, was discovered in the 1960s, linking the metabolism of folate, vitamin B12, methionine and homocysteine. However, the existence or physiological significance of this phenomenon has been unknown in bacteria, which synthesize folate de novo. Here we identify the methylfolate trap as a novel determinant of the bacterial intrinsic death by sulfonamides, antibiotics that block de novo folate synthesis. Genetic mutagenesis, chemical complementation, and metabolomic profiling revealed trap-mediated metabolic imbalances, which induced thymineless death, a phenomenon in which rapidly growing cells succumb to thymine starvation. Restriction of B12 bioavailability, required for preventing trap formation, using an “antivitamin B12” molecule, sensitized intracellular bacteria to sulfonamides. Since boosting the bactericidal activity of sulfonamides through methylfolate trap induction can be achieved in Gram-negative bacteria and mycobacteria, it represents a novel strategy to render these pathogens more susceptible to existing sulfonamides.

Original languageEnglish (US)
Article numbere1005949
JournalPLoS pathogens
Issue number10
StatePublished - Oct 2016

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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