Journal Article

Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs

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

2016

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Anti-Bacterial Agents - pharmacology / Antibiotics / Bacteria / Bacteria - drug effects / Bacteria - metabolism / Bacterial infections / Bioavailability / Biology and Life Sciences / Cardiovascular diseases / Colleges & universities / Dementia disorders / Dosage and administration / Drug resistance / Drug Resistance, Microbial - physiology / Drug therapy / Folic Acid - metabolism / Funding / Genomes / Homocysteine / Homocysteine - metabolism / Infections / Medicine / Medicine and Health Sciences / Metabolism / Methionine - metabolism / Microbial metabolism / Microbial Sensitivity Tests / Molecular biology / Mortality / Mutagenesis / Mycobacteria / Organic chemistry / Physical Sciences / Physiological aspects / Standard deviation / Sulfonamides / Vitamin B / Vitamin B 12 - metabolism