ArticleMolecular pharmacology2011
The diamidine diminazene aceturate is a substrate for the high-affinity pentamidine transporter: implications for the development of high resistance levels in trypanosomes.
Article in Molecular pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 54 citations in OpenAlex.
- Article
- Trypanocide Use and Molecular Characterization of Trypanosomes Resistant to Diminazene Aceturate in Cattle in Northern Côte D'Ivoire.Tropical medicine and infectious disease · 2024Article
- Drug resistance in animal trypanosomiases: Epidemiology, mechanisms and control strategies.International journal for parasitology. Drugs and drug resistance · 2024Review
- Structural insights into drug transport by an aquaglyceroporin.Nature communications · 2024Article
- Laboratory Selection of Trypanosomatid Pathogens for Drug Resistance.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Article
- The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History.Tropical medicine and infectious disease · 2020Review
- Investigation of 5'-Norcarbocyclic Nucleoside Analogues as Antiprotozoal and Antibacterial Agents.Molecules (Basel, Switzerland) · 2019Article
- Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy.International journal for parasitology. Drugs and drug resistance · 2017Article
- Exploiting the Achilles' heel of membrane trafficking in trypanosomes.Current opinion in microbiology · 2016Review
- The animal trypanosomiases and their chemotherapy: a review.Parasitology · 2016Review
- Reduced Mitochondrial Membrane Potential Is a Late Adaptation of Trypanosoma brucei brucei to Isometamidium Preceded by Mutations in the γ Subunit of the F1Fo-ATPase.PLoS neglected tropical diseases · 2016Article
- 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.Molecular microbiology · 2015Article
- Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei.Frontiers in pharmacology · 2015Review
- The comprehensive analysis of DEG/ENaC subunits in Hydra reveals a large variety of peptide-gated channels, potentially involved in neuromuscular transmission.BMC biology · 2014Article
- Functional expression of TcoAT1 reveals it to be a P1-type nucleoside transporter with no capacity for diminazene uptake.International journal for parasitology. Drugs and drug resistance · 2013Article
- Pharmacokinetics, Trypanosoma brucei gambiense efficacy, and time of drug action of DB829, a preclinical candidate for treatment of second-stage human African trypanosomiasis.Antimicrobial agents and chemotherapy · 2013Article
- Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story.Trends in parasitology · 2013Review
- Pyrimidine salvage in Trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines.Molecular pharmacology · 2013Article
- Aquaporin 2 mutations in Trypanosoma brucei gambiense field isolates correlate with decreased susceptibility to pentamidine and melarsoprol.PLoS neglected tropical diseases · 2013Article
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Authors and funding
11 authors at 4 institutions in 4 countries.
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Abstract
African trypanosomiasis is a disease of humans and livestock in many areas south of the Sahara. Resistance to the few existing drugs is a major impediment to the control of these diseases, and we investigated how resistance to the main veterinary drug diminazene aceturate correlates with changes in drug transport in resistant strains. The strain tbat1(-/-), lacking the TbAT1/P2 aminopurine transporter implicated previously in diminazene transport, was adapted to higher levels of diminazene resistance. The resulting cell line was designated ABR and was highly cross-resistant to other diamidines and moderately resistant to cymelarsan. Procyclic trypanosomes were shown to be a convenient model to study diamidine uptake in Trypanosoma brucei brucei given the lack of TbAT1/P2 and a 10-fold higher activity of the high-affinity pentamidine transporter (HAPT1). Diminazene could be transported by HAPT1 in procyclic trypanosomes. This drug transport activity was lacking in the ABR line, as reported previously for the pentamidine-adapted line B48. The K(m) for diminazene transport in bloodstream tbat1(-/-) trypanosomes was consistent with uptake by HAPT1. Diminazene transport in ABR and B48 cells was reduced compared with tbat1(-/-), but their resistance phenotype was different: B48 displayed higher levels of resistance to pentamidine and the melaminophenyl arsenicals, whereas ABR displayed higher resistance to diminazene. These results establish a loss of HAPT1 function as a contributing factor to diminazene resistance but equally demonstrate for the first time that adaptations other than those determining the initial rates of drug uptake contribute to diamidine and arsenical resistance in African trypanosomes.
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