ArticleAntimicrobial agents and chemotherapy2002
Novel Saccharomyces cerevisiae screen identifies WR99210 analogues that inhibit Mycobacterium tuberculosis dihydrofolate reductase.
Article in Antimicrobial agents and chemotherapy, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 58 citations in OpenAlex.
- Identification of potential inhibitors of dihydrofolate reductase (DHFR) through blocking the folate biosynthetic pathway ofRSC advances · 2025Article
- Pharmacological validation of dihydrofolate reductase as a drug target inAntimicrobial agents and chemotherapy · 2024Article
- Potency boost of aProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Revitalizing antifolates through understanding mechanisms that govern susceptibility and resistance.MedChemComm · 2019Review
- Antimycobacterial Metabolism: Illuminating Mycobacterium tuberculosis Biology and Drug Discovery.Trends in microbiology · 2017Review
- A Focused Screen Identifies Antifolates with Activity on Mycobacterium tuberculosis.ACS infectious diseases · 2015Article
- Design and Synthesis of a Focused Library of Diamino Triazines as Potential Mycobacterium tuberculosis DHFR Inhibitors.ACS medicinal chemistry letters · 2015Article
- The identification of novel Mycobacterium tuberculosis DHFR inhibitors and the investigation of their binding preferences by using molecular modelling.Scientific reports · 2015Article
- Mycobacterium tuberculosis folate metabolism and the mechanistic basis for para-aminosalicylic acid susceptibility and resistance.Antimicrobial agents and chemotherapy · 2015Review
- para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis.The Journal of biological chemistry · 2013Article
- Article
- Triclosan inhibition of mycobacterial InhA in Saccharomyces cerevisiae: yeast mitochondria as a novel platform for in vivo antimycolate assays.Letters in applied microbiology · 2010Article
- The essential mycobacterial genes, fabG1 and fabG4, encode 3-oxoacyl-thioester reductases that are functional in yeast mitochondrial fatty acid synthase type 2.Molecular genetics and genomics : MGG · 2009Article
- Heterologous expression of mycobacterial proteins in Saccharomyces cerevisiae reveals two physiologically functional 3-hydroxyacyl-thioester dehydratases, HtdX and HtdY, in addition to HadABC and HtdZ.Journal of bacteriology · 2009Article
- targetTB: a target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis.BMC systems biology · 2008Article
- Function of heterologous Mycobacterium tuberculosis InhA, a type 2 fatty acid synthase enzyme involved in extending C20 fatty acids to C60-to-C90 mycolic acids, during de novo lipoic acid synthesis in Saccharomyces cerevisiae.Applied and environmental microbiology · 2008Article
- Identification of a novel mycobacterial 3-hydroxyacyl-thioester dehydratase, HtdZ (Rv0130), by functional complementation in yeast.Journal of bacteriology · 2008Article
- Functional analysis of the Mycobacterium tuberculosis FAD-dependent thymidylate synthase, ThyX, reveals new amino acid residues contributing to an extended ThyX motif.Journal of bacteriology · 2008Article
- Evaluation of the activities of pyrimethamine analogs against Plasmodium vivax and Plasmodium falciparum dihydrofolate reductase-thymidylate synthase using in vitro enzyme inhibition and bacterial complementation assays.Antimicrobial agents and chemotherapy · 2006Article
- System for expression of microsporidian methionine amino peptidase type 2 (MetAP2) in the yeast Saccharomyces cerevisiae.Antimicrobial agents and chemotherapy · 2006Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The ongoing selection of multidrug-resistant strains of Mycobacterium tuberculosis has markedly reduced the effectiveness of the standard treatment regimens. Thus, there is an urgent need for new drugs that are potent inhibitors of M. tuberculosis, that exhibit favorable resistance profiles, and that are well tolerated by patients. One promising drug target for treatment of mycobacterial infections is dihydrofolate reductase (DHFR; EC 1.5.1.3), a key enzyme in folate utilization. DHFR is an important drug target in many pathogens, but it has not been exploited in the search for drugs effective against M. tuberculosis. The triazine DHFR inhibitor WR99210 has been shown to be effective against other mycobacteria. We show here that WR99210 is also a potent inhibitor of M. tuberculosis and Mycobacterium bovis BCG growth in vitro and that resistance to WR99210 occurred less frequently than resistance to either rifampin or isoniazid. Screening of drugs with M. tuberculosis cultures is slow and requires biosafety level 3 facilities and procedures. We have developed an alternative strategy: initial screening in an engineered strain of the budding yeast Saccharomyces cerevisiae that is dependent on the M. tuberculosis DHFR for its growth. Using this system, we have screened 19 compounds related to WR99210 and found that 7 of these related compounds are also potent inhibitors of the M. tuberculosis DHFR. These studies suggest that compounds of this class are excellent potential leads for further development of drugs effective against M. tuberculosis.
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