ArticleCell chemical biology2019
Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents.
Article in Cell chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 66 citations in OpenAlex.
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- Expanding the Landscape of Dual Action Antifolate Antibacterials through 2,4-Diamino-1,6-dihydro-1,3,5-triazines.ACS infectious diseases · 2025Article
- In Silico Investigation of Phytochemicals From Clinically Tested Herbal Extracts as Potential Dihydrofolate Reductase Inhibitors for Buruli Ulcer.BioMed research international · 2025Article
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- Redirecting raltitrexed from cancer cell thymidylate synthase toScience advances · 2024Article
- The aminosalicylate - folate connection.Drug metabolism reviews · 2024Review
- Pharmacological validation of dihydrofolate reductase as a drug target inAntimicrobial agents and chemotherapy · 2024Article
- Polypharmacology-Driven Discovery and Design of Highly Selective, Dual and Multitargeting Inhibitors ofCurrent drug targets · 2024Review
- Multi-target Compounds against Trypanosomatid Parasites andCurrent drug targets · 2024Review
- Causal associations of gut microbiota and pulmonary tuberculosis: a two-sample Mendelian randomization study.Frontiers in microbiology · 2024Article
- Competition between HAntibiotics (Basel, Switzerland) · 2023Article
- Whole genome sequencing reveals candidate genes involving in PAS resistance in M. Tuberculosis isolated from patients in Thailand.World journal of microbiology & biotechnology · 2023Article
- Association between mutations in aEmerging microbes & infections · 2023Article
- Article
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- Dual-TargetInternational journal of molecular sciences · 2023Article
- Comprehensive essentiality analysis of themBio · 2023Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity.
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Registered trials
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