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.
Highlights
Sulfonamides, or SULFA drugs, were the first chemical substances systematically used to treat and prevent bacterial infections [1, 2], but the use of these drugs gradually declined because of the emergence of resistant organisms [3]
We found that disruption of 5,10-methenyltetrahydrofolate synthase (MTHFS), an enzyme responsible for the conversion of N5-formyltetrahydrofolate (5-CHO-H4PteGlun) to N5,N10-methenyltetrahydrofolate (5,10-CH+-H4PteGlun) in the folate-dependent one-carbon metabolic network (Fig 1A), led to severe defects in cellular folate homeostasis weakening the intrinsic antifolate resistance in bacteria [12]
In trans expression of metH completely restored wild type SULFA resistance to RvΔmetH (Table 1, Fig 3A). These results indicated that the methylfolate trap was able to sensitize M. tuberculosis H37Rv to SULFA drugs
Summary
Sulfonamides, or SULFA drugs, were the first chemical substances systematically used to treat and prevent bacterial infections [1, 2], but the use of these drugs gradually declined because of the emergence of resistant organisms [3]. TMP has been the only SULFA booster approved for clinical use, and resistance to both TMP and SULFAs has emerged [7]. A recent strategy for developing antibiotic boosters is “resisting resistance” [11], in which inhibitors that suppress resistance mechanisms are used to sensitize host bacteria to antibiotics. Our laboratory recently suggested that targeting antifolate resistance may lead to the development of such adjunctive chemotherapies for SULFAs and TMP [12]. We found that disruption of 5,10-methenyltetrahydrofolate synthase (MTHFS), an enzyme responsible for the conversion of N5-formyltetrahydrofolate (5-CHO-H4PteGlun) to N5,N10-methenyltetrahydrofolate (5,10-CH+-H4PteGlun) in the folate-dependent one-carbon metabolic network (Fig 1A), led to severe defects in cellular folate homeostasis weakening the intrinsic antifolate resistance in bacteria [12]
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