Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Guzzo, MB; Nguyen, HT; Pham, TH; Wyszczelska-Rokiel, M; Jakubowski, H; Wolff, KA; Ogwang, S; Timpona, JL; Gogula, S; Jacobs, MR; Ruetz, M; Kräutler, B; Jacobsen, DW; Zhang, G-F; Nguyen, L
Published Date
- October 2016
Published In
Volume / Issue
- 12 / 10
Start / End Page
- e1005949 -
PubMed ID
- 27760199
Pubmed Central ID
- PMC5070874
Electronic International Standard Serial Number (EISSN)
- 1553-7374
Digital Object Identifier (DOI)
- 10.1371/journal.ppat.1005949
Language
- eng
Conference Location
- United States