ArticleMolecular microbiology2015
Functional analysis of drug resistance-associated mutations in the Trypanosoma brucei adenosine transporter 1 (TbAT1) and the proposal of a structural model for the protein.
Article in Molecular microbiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 57 citations in OpenAlex.
- Article
- TargetingFrontiers in microbiology · 2026Review
- Identification of Potential Vectors and Species Density of Tsetse Fly, Prevalence, and Genetic Diversity of Drug-Resistant Trypanosomes in Kenya.Pathogens (Basel, Switzerland) · 2025Article
- Sustainable Antiparasitic Agents from an Agro-Industrial Waste: Mitochondria-Targeting Cashew Nutshell Liquid-Derived Phosphonium and Ammonium Salts.Journal of medicinal chemistry · 2025Article
- Guanine derivatives as promising candidates for the development of purine-based antimalarial drugs.Frontiers in parasitology · 2025Article
- Drug resistance in animal trypanosomiases: Epidemiology, mechanisms and control strategies.International journal for parasitology. Drugs and drug resistance · 2024Review
- Cloning and Characterization ofInternational journal of molecular sciences · 2023Article
- TheMolecules (Basel, Switzerland) · 2022Article
- Systematic Review and Meta-Analysis on Human African Trypanocide Resistance.Pathogens (Basel, Switzerland) · 2022Review
- Nucleoside Transport and Nucleobase Uptake Null Mutants inInternational journal of molecular sciences · 2022Article
- Differences in Transporters Rather than Drug Targets Are the Principal Determinants of the Different Innate Sensitivities ofInternational journal of molecular sciences · 2022Article
- An Update on African Trypanocide Pharmaceutics and Resistance.Frontiers in veterinary science · 2022Review
- Comprehensive characterization of purine and pyrimidine transport activities in Trichomonas vaginalis and functional cloning of a trichomonad nucleoside transporter.Molecular microbiology · 2021Article
- Article
- The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History.Tropical medicine and infectious disease · 2020Review
- Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness.Nature communications · 2019Article
- Investigation of 5'-Norcarbocyclic Nucleoside Analogues as Antiprotozoal and Antibacterial Agents.Molecules (Basel, Switzerland) · 2019Article
- Potent Antitrypanosomal Activities of 3-Aminosteroids against African Trypanosomes: Investigation of Cellular Effects and of Cross-Resistance with Existing Drugs.Molecules (Basel, Switzerland) · 2019Article
- Protean permeases: Diverse roles for membrane transport proteins in kinetoplastid protozoa.Molecular and biochemical parasitology · 2019Review
- Drug resistance in protozoan parasites.Emerging topics in life sciences · 2017Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 6 countries.
Funding
Abstract
The Trypanosoma brucei aminopurine transporter P2/TbAT1 has long been implicated in the transport of, and resistance to, the diamidine and melaminophenyl arsenical classes of drugs that form the backbone of the pharmacopoeia against African trypanosomiasis. Genetic alterations including deletions and single nucleotide polymorphisms (SNPs) have been observed in numerous strains and clinical isolates. Here, we systematically investigate each reported mutation and assess their effects on transporter function after expression in a tbat1(-/-) T. brucei line. Out of a set of six reported SNPs from a reported 'resistance allele', none significantly impaired sensitivity to pentamidine, diminazene or melarsoprol, relative to the TbAT1-WT allele, although several combinations, and the deletion of the codon for residue F316, resulted in highly significant impairment. These combinations of SNPs, and ΔF316, also strongly impaired the uptake of [(3)H]-adenosine and [(3)H]-diminazene, identical to the tbat1(-/-) control. The TbAT1 protein model predicted that residues F19, D140 and F316 interact with the substrate of the transporter. Mutation of D140 to alanine resulted in an inactive transporter, whereas the mutation F19A produced a transporter with a slightly increased affinity for [(3)H]-diminazene but reduced the uptake rate. The results presented here validate earlier hypotheses of drug binding motifs for TbAT1.
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