ArticlePLoS pathogens2010
A molecular mechanism for eflornithine resistance in African trypanosomes.
Article in PLoS pathogens, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers.
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Who cites it
88 citing papers in PubMed, 183 citations in OpenAlex.
- Canalesolide A, a Structurally Unique Polyhydroxy Macrolide from the Marine Cyanobacterium Okeania sp. with Potent Antitrypanosomal Activity.Journal of the American Chemical Society · 2026Article
- Covalent Inhibitors in Antimicrobial Drug Development-Beyond β-Lactams.Molecules (Basel, Switzerland) · 2026Review
- Pathogenic Significance of Trypanosomatids: Progress in Drug Resistance, Control Strategies, and Artificial Intelligence.Interdisciplinary perspectives on infectious diseases · 2026Review
- To Explore Potential Natural Inhibitors of Cysteine Proteases to Combat Human African Trypanosomiasis and Chagas Disease.Current medicinal chemistry · 2026Review
- Evolution, composition and functions of cullin E3 ubiquitin ligases in trypanosomes.Scientific reports · 2025Article
- Transforming the chemotherapy of human African trypanosomiasis.Clinical microbiology reviews · 2025Review
- Lead Optimization of the 5-Phenylpyrazolopyrimidinone NPD-2975 toward Compounds with Improved Antitrypanosomal Efficacy.Journal of medicinal chemistry · 2024Article
- Synthesis and Biophysical and Biological Studies ofJournal of medicinal chemistry · 2023Article
- Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy.Journal of medicinal chemistry · 2023Article
- Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.International journal of molecular sciences · 2023Review
- Identification of transport systems involved in eflornithine delivery across the blood-brain barrier.Frontiers in drug delivery · 2023Article
- Cloning and Characterization ofInternational journal of molecular sciences · 2023Article
- Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei.Bioorganic & medicinal chemistry letters · 2023Article
- Systematic Review and Meta-Analysis on Human African Trypanocide Resistance.Pathogens (Basel, Switzerland) · 2022Review
- Cellular barcoding of protozoan pathogens reveals the within-host population dynamics ofCell reports methods · 2022Article
- Current Treatments to Control African Trypanosomiasis and One Health Perspective.Microorganisms · 2022Review
- Polyamine Metabolism inMedical sciences (Basel, Switzerland) · 2022Review
- Trypanosoma brucei: Metabolomics for analysis of cellular metabolism and drug discovery.Metabolomics : Official journal of the Metabolomic Society · 2022Review
- Differences in Transporters Rather than Drug Targets Are the Principal Determinants of the Different Innate Sensitivities ofInternational journal of molecular sciences · 2022Article
- Laboratory Selection of Trypanosomatid Pathogens for Drug Resistance.Pharmaceuticals (Basel, Switzerland) · 2022Review
28 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
Human African trypanosomiasis, endemic to sub-Saharan Africa, is invariably fatal if untreated. Its causative agent is the protozoan parasite Trypanosoma brucei. Eflornithine is used as a first line treatment for human African trypanosomiasis, but there is a risk that resistance could thwart its use, even when used in combination therapy with nifurtimox. Eflornithine resistant trypanosomes were selected in vitro and subjected to biochemical and genetic analysis. The resistance phenotype was verified in vivo. Here we report the molecular basis of resistance. While the drug's target, ornithine decarboxylase, was unaltered in resistant cells and changes to levels of metabolites in the targeted polyamine pathway were not apparent, the accumulation of eflornithine was shown to be diminished in resistant lines. An amino acid transporter gene, TbAAT6 (Tb927.8.5450), was found to be deleted in two lines independently selected for resistance. Ablating expression of this gene in wildtype cells using RNA interference led to acquisition of resistance while expression of an ectopic copy of the gene introduced into the resistant deletion lines restored sensitivity, confirming the role of TbAAT6 in eflornithine action. Eflornithine resistance is easy to select through loss of a putative amino acid transporter, TbAAT6. The loss of this transporter will be easily identified in the field using a simple PCR test, enabling more appropriate chemotherapy to be administered.
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