title: Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Marissa B
authors.initials: MB
authors.lastname: Guzzo
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Hoa T
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Thanh H
authors.initials: TH
authors.lastname: Pham
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, New Jersey Medical School, Newark, New Jersey, United States of America.|Department of Environmental Chemistry, University of Lodz, Lodz, Poland.
authors.forename: Monika
authors.identifier: http://orcid.org/0000-0002-3766-3647
authors.initials: M
authors.lastname: Wyszczelska-Rokiel
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, New Jersey Medical School, Newark, New Jersey, United States of America.|Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland.|Department of Biochemistry and Biotechnology, Life Sciences University, Poznań, Poland.
authors.forename: Hieronim
authors.initials: H
authors.lastname: Jakubowski
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Kerstin A
authors.initials: KA
authors.lastname: Wolff
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Sam
authors.initials: S
authors.lastname: Ogwang
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Timpona
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Soumya
authors.initials: S
authors.lastname: Gogula
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jacobs
authors.affiliation: Institute of Organic Chemistry and Center of Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Ruetz
authors.affiliation: Institute of Organic Chemistry and Center of Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kräutler
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Jacobsen
authors.affiliation: Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Guo-Fang
authors.initials: GF
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Liem
authors.initials: L
authors.lastname: Nguyen
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism*; D004352:Drug Resistance, Microbial / Q000502:physiology*; D005492:Folic Acid / Q000378:metabolism*; D006710:Homocysteine / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D014805:Vitamin B 12 / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D006710:Homocysteine; D005492:Folic Acid; D008715:Methionine; D014805:Vitamin B 12