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These metabolic imbalances induced thymineless death, which was reversible with exogenous thymine supplementation. Chemical restriction of vitamin B12, an important molecule required for prevention of the methylfolate trap, sensitized intracellular bacteria to sulfonamides. Thus, pharmaceutical promotion of the methylfolate trap represents a novel folate antagonistic strategy to render pathogenic bacteria more susceptible to available, clinically approved sulfonamides.

Citation: Guzzo MB, Nguyen HT, Pham TH, Wyszczelska-Rokiel Disease meniere s, Jakubowski H, Wolff KA, et al. PLoS Pathog 12(10): e1005949. This is an open access article distributed under the terms disease meniere s the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are disease meniere s. Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This work was supported by National Institutes of Health (Grants R01AI087903 and R21AI119287) to LN. JLT and SG were fellows of the HHMI Biological Science Initiative and supported by the Case Summer Program in Undergraduate Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.

Abbreviations: Disease meniere s, tetrahydrofolate (green) serves as carrier for one-carbon groups. Two different types of TS have been described: ThyA and ThyX. While most organisms contain either ThyA or ThyX, some organisms including M.

Reactions directly involved in the methylfolate trap (MS) and thymineless death (TS) are highlighted in yellow and red, respectively. A pool of antifolate sensitive mutants was replicated onto NE plates, in top-down order: (i) control, (ii) SCP, (iii) SCP plus Disease meniere s, (iv) SCP plus 5-CHO-H4PteGlu1, (v) SCP plus 5-CH3-H4PteGlu1, and (vi) SCP plus disease meniere s. SCP was used at 10.

However, they become more bactericidal in rich media, particularly when cellular levels of glycine, methionine and purines are high. Classified as folate antagonists, or antifolates, these drugs inhibit bacterial de novo folate biosynthesis (Fig 1A), which is absent in mammalian cells.

While SULFAs target dihydropteroate synthase (DHPS), TMP inhibits dihydrofolate reductase (DHFR). Both of these enzymes are required for the formation of folate, a vitamin essential for cell growth across all kingdoms of life. The dominant form of folate in the cell is tetrahydrofolate (H4PteGlun, with n indicating the number of glutamate moieties).

This reaction depends disease meniere s three components: (i) N5-methyltetrahydrofolate (5-CH3-H4PteGlun), a methyl donor, (ii) B12, the intermediate carrier for the methyl group, and (iii) the disease meniere s activity provided by MetH. Although it has been studied in humans, and ex vivo in withdraw cells, the existence or physiological significance of the methylfolate trap in bacteria has never been documented.

Here we disease meniere s the identification of the methylfolate trap as a novel determinant of SULFA resistance in bacteria. Upon its disease meniere s in response to SULFAs, the methylfolate trap causes impaired homeostasis of folate and related metabolites, including a progressive accumulation of Hcy-thiolactone that is known to be cytotoxic. More importantly, cells undergoing the methylfolate trap are also unable to deplete glycine and nucleotides, and suffer thymineless death induced by SULFAs.

This metabolic blockage renders pathogenic bacteria, including M. Furthermore, chemical induction of the methylfolate trap, as shown in our experiments, represents a viable method for boosting the antimicrobial activity of available, clinically approved SULFAs against bacterial pathogens.

A screen of 13,500 Himar1-transposon M. After 2 rounds of drug susceptibility tests, the disrupted genes were mapped using nested PCRs, followed by sequencing. Of the 50 chromosomal loci identified as being responsible for the intrinsic Denavir (Penciclovir)- FDA resistance of M. Overall, the resistance determinants were evenly distributed throughout the M.

In addition, insertions were mapped to chromosomal loci potentially affecting regulatory or signaling processes (mprA, sigB, sigE, pknG, pafA, pup, pcrB, and pcrA), transsulfuration (cysH and mshB), transport (mmpL and pstC), and other cellular activities (S1 Table). Mutants were further profiled using chemical complementation. These analyses provided useful geno-chemo-phenotypic information to each individual antifolate resistance determinant (S1 Table).

The mutants were unable to use exogenous 5-CH3-H4PteGlu1 to antagonize SULFAs (Fig 1C, panel (v)). Whereas the metH-encoded enzyme catalyzes the reaction, disease meniere s is required for the de novo biosynthesis of B12, the cofactor required for MetH activity.

The CH3- group in 5-CH3-H4PteGlun is first transferred to the B12 cofactor, which further transfers it to homocysteine (Hcy) to make methionine (Met). The MetH reaction thereby recycles 5-CH3-H4PteGlun back to free H4PteGlun which continues disease meniere s flow of the one-carbon network. The strains exhibited increased SULFA susceptibility and impaired 5-CH3-H4PteGlu1 utilization. Approximately 5x103 cells were spotted onto NE medium added with 10. Unlike wild disease meniere s and other mutants, these mutants were unable to use 5-CH3-H4PteGlu1 to antagonize SCP.

Exogenous B12 restored 5-CH3-H4PteGlu1 utilization and SCP resistance to cobIJ but not metH mutants. Growing cultures of M. Disease meniere s shows the combined levels of all 5-CH3-H4PteGlun species (top), all non-methyl folate species (middle), and the total folate (bottom). Bars represent means of biological triplicates with standard deviations. Paper discs were embedded with 0. Exogenous B12 and 5-CH3-H4PteGlun were used at 0.

Genetic complementation was achieved by in trans expression of metH or cobIJ. To detect the methylfolate trap at a metabolic level, M. Cultures were immediately harvested and total folate was extracted in subdued light. Both metH and cobIJ exhibited 5-CH3-H4PteGlun accumulation compared to wild type M.

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