Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs

PLoS Pathogens

Joseph L. Timpona¹  Hieronim Jakubowski²  Kerstin A. Wolff³  Monika Wyszczelska-Rokiel³  Marissa B. Guzzo⁴  Hoa T. Nguyen⁴  Markus Ruetz⁴  Bernhard Kräutler⁴  Michael R. Jacobs⁴  Soumya Gogula⁴  Thanh H. Pham⁴  Donald W. Jacobsen⁵  Sam Ogwang⁶  Guo-Fang Zhang⁷  Liem Nguyen⁷ 

[1] Department of Biochemistry and Biotechnology, Life Sciences University, Poznań, Poland;Department of Environmental Chemistry, University of Lodz, Lodz, Poland;Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, New Jersey Medical School, Newark, New Jersey, United States of America;Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America;Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America;Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland;Institute of Organic Chemistry and Center of Molecular Biosciences, University of Innsbruck, Innsbruck, Austria

关键词: Salmonella typhimurium;    Methionine;    Drug metabolism;    Mycobacterium tuberculosis;    Macrophages;    Cell metabolism;    Antibiotics;    Bacterial pathogens;   

DOI  :  10.1371/journal.ppat.1005949

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY