ArticleThe Journal of biological chemistry2016
The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 22 citations in OpenAlex.
- Comparative metabolism of conjugated and unconjugated pterins in Crithidia, Leishmania and African trypanosomes.PLoS neglected tropical diseases · 2025Article
- In silico prediction of the metabolism of Blastocrithidia nonstop, a trypanosomatid with non-canonical genetic code.BMC genomics · 2024Article
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- Identification of Active Compounds against Melanoma Growth by Virtual Screening for Non-Classical Human DHFR Inhibitors.International journal of molecular sciences · 2022Article
- Sesquiterpene Lactones with Dual Inhibitory Activity against theMolecules (Basel, Switzerland) · 2021Article
- Analysis of Fox genes in Schmidtea mediterranea reveals new families and a conserved role of Smed-foxO in controlling cell death.Scientific reports · 2021Article
- Experimental Strategies to Explore Drug Action and Resistance in Kinetoplastid Parasites.Microorganisms · 2020Review
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- Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals.Antimicrobial agents and chemotherapy · 2018Article
- Molecular docking to Toxoplasma gondii thymidylate synthase-dihydrofolate reductase and efficacy of raltitrexed in infected mice.Parasitology research · 2018Article
- A Riboswitch-based Inducible Gene Expression System for Trypanosoma brucei.The Journal of eukaryotic microbiology · 2018Article
- Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To InhibitACS omega · 2017Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The aim of this study was to identify and characterize mechanisms of resistance to antifolate drugs in African trypanosomes. Genome-wide RNAi library screens were undertaken in bloodstream form Trypanosoma brucei exposed to the antifolates methotrexate and raltitrexed. In conjunction with drug susceptibility and folate transport studies, RNAi knockdown was used to validate the functions of the putative folate transporters. The transport kinetics of folate and methotrexate were further characterized in whole cells. RNA interference target sequencing experiments identified a tandem array of genes encoding a folate transporter family, TbFT1-3, as major contributors to antifolate drug uptake. RNAi knockdown of TbFT1-3 substantially reduced folate transport into trypanosomes and reduced the parasite's susceptibly to the classical antifolates methotrexate and raltitrexed. In contrast, knockdown of TbFT1-3 increased susceptibly to the non-classical antifolates pyrimethamine and nolatrexed. Both folate and methotrexate transport were inhibited by classical antifolates but not by non-classical antifolates or biopterin. Thus, TbFT1-3 mediates the uptake of folate and classical antifolates in trypanosomes, and TbFT1-3 loss-of-function is a mechanism of antifolate drug resistance.
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Registered trials
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