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Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs.

Publication ,  Journal Article
Guzzo, MB; Nguyen, HT; Pham, TH; Wyszczelska-Rokiel, M; Jakubowski, H; Wolff, KA; Ogwang, S; Timpona, JL; Gogula, S; Jacobs, MR; Ruetz, M ...
Published in: PLoS Pathog
October 2016

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.

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Published In

PLoS Pathog

DOI

EISSN

1553-7374

Publication Date

October 2016

Volume

12

Issue

10

Start / End Page

e1005949

Location

United States

Related Subject Headings

  • Vitamin B 12
  • Virology
  • Microbial Sensitivity Tests
  • Methionine
  • Homocysteine
  • Folic Acid
  • Drug Resistance, Microbial
  • Bacteria
  • Anti-Bacterial Agents
  • 3207 Medical microbiology
 

Citation

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Chicago
ICMJE
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Guzzo, M. B., Nguyen, H. T., Pham, T. H., Wyszczelska-Rokiel, M., Jakubowski, H., Wolff, K. A., … Nguyen, L. (2016). Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs. PLoS Pathog, 12(10), e1005949. https://doi.org/10.1371/journal.ppat.1005949
Guzzo, Marissa B., Hoa T. Nguyen, Thanh H. Pham, Monika Wyszczelska-Rokiel, Hieronim Jakubowski, Kerstin A. Wolff, Sam Ogwang, et al. “Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs.PLoS Pathog 12, no. 10 (October 2016): e1005949. https://doi.org/10.1371/journal.ppat.1005949.
Guzzo MB, Nguyen HT, Pham TH, Wyszczelska-Rokiel M, Jakubowski H, Wolff KA, et al. Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs. PLoS Pathog. 2016 Oct;12(10):e1005949.
Guzzo, Marissa B., et al. “Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs.PLoS Pathog, vol. 12, no. 10, Oct. 2016, p. e1005949. Pubmed, doi:10.1371/journal.ppat.1005949.
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. Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs. PLoS Pathog. 2016 Oct;12(10):e1005949.

Published In

PLoS Pathog

DOI

EISSN

1553-7374

Publication Date

October 2016

Volume

12

Issue

10

Start / End Page

e1005949

Location

United States

Related Subject Headings

  • Vitamin B 12
  • Virology
  • Microbial Sensitivity Tests
  • Methionine
  • Homocysteine
  • Folic Acid
  • Drug Resistance, Microbial
  • Bacteria
  • Anti-Bacterial Agents
  • 3207 Medical microbiology