ArticleThe Journal of antimicrobial chemotherapy2016
Nitroheterocyclic drug resistance mechanisms in Trypanosoma brucei.
Article in The Journal of antimicrobial chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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54 citing papers in PubMed, 77 citations in OpenAlex.
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- Canalesolide A, a Structurally Unique Polyhydroxy Macrolide from the Marine Cyanobacterium Okeania sp. with Potent Antitrypanosomal Activity.Journal of the American Chemical Society · 2026Article
- A cell surface transporter mediates phenanthridine resistance in African trypanosomes.npj antimicrobials and resistance · 2026Article
- Phenotypic profiling of Pathogen Box compounds MMV667494 and MMV028694 in bloodstream-formExperimental biology and medicine (Maywood, N.J.) · 2026Article
- Untargeted metabolomics for triaging of cytochrome b inhibitors during Chagas' disease drug discovery.PLoS neglected tropical diseases · 2026Article
- Pathogenic Significance of Trypanosomatids: Progress in Drug Resistance, Control Strategies, and Artificial Intelligence.Interdisciplinary perspectives on infectious diseases · 2026Review
- Old drugs, new weapons: current trends in repurposing therapies against antimicrobial resistance.Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques · 2026Review
- A CRISPR-based diagnostic tool to survey drug resistance in human African trypanosomiasis.Antimicrobial agents and chemotherapy · 2025Article
- Fexinidazole results in specific effects on DNA synthesis and DNA damage in the African trypanosome.PLoS neglected tropical diseases · 2025Article
- Cytological profiling of trypanocidal principles fromPhytomedicine plus : international journal of phytotherapy and phytopharmacology · 2025Article
- Transforming the chemotherapy of human African trypanosomiasis.Clinical microbiology reviews · 2025Review
- Traditional Medicinal Ranunculaceae Species from Romania and Their In Vitro Antioxidant, Antiproliferative, and Antiparasitic Potential.International journal of molecular sciences · 2024Article
- Drug Repurposing in the Chemotherapy of Infectious Diseases.Molecules (Basel, Switzerland) · 2024Review
- Discovery of an orally active nitrothiophene-based antitrypanosomal agent.European journal of medicinal chemistry · 2024Article
- Multiparameter ranking of carbazoles for anti-trypanosome lead discovery.Frontiers in drug discovery · 2024Article
- Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy.Journal of medicinal chemistry · 2023Article
- The critical role of mode of action studies in kinetoplastid drug discovery.Frontiers in drug discovery · 2023Article
- Antimicrobial Peptides (AMPs): Potential Therapeutic Strategy against Trypanosomiases?Biomolecules · 2023Review
- The pipeline for drugs for control and elimination of neglected tropical diseases: 1. Anti-infective drugs for regulatory registration.Parasites & vectors · 2023Review
- Targeting trypanosomes: how chemogenomics and artificial intelligence can guide drug discovery.Biochemical Society transactions · 2023Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
objectivesThe objective of this study was to identify the mechanisms of resistance to nifurtimox and fexinidazole in African trypanosomes.
methodsBloodstream-form Trypanosoma brucei were selected for resistance to nifurtimox and fexinidazole by stepwise exposure to increasing drug concentrations. Clones were subjected to WGS to identify putative resistance genes. Transgenic parasites modulating expression of genes of interest were generated and drug susceptibility phenotypes determined.
resultsNifurtimox-resistant (NfxR) and fexinidazole-resistant (FxR) parasites shared reciprocal cross-resistance suggestive of a common mechanism of action. Previously, a type I nitroreductase (NTR) has been implicated in nitro drug activation. WGS of resistant clones revealed that NfxR parasites had lost >100 kb from one copy of chromosome 7, rendering them hemizygous for NTR as well as over 30 other genes. FxR parasites retained both copies of NTR, but lost >70 kb downstream of one NTR allele, decreasing NTR transcription by half. A single knockout line of NTR displayed 1.6- and 1.9-fold resistance to nifurtimox and fexinidazole, respectively. Since NfxR and FxR parasites are ∼6- and 20-fold resistant to nifurtimox and fexinidazole, respectively, additional factors must be involved. Overexpression and knockout studies ruled out a role for a putative oxidoreductase (Tb927.7.7410) and a hypothetical gene (Tb927.1.1050), previously identified in a genome-scale RNAi screen.
conclusionsNTR was confirmed as a key resistance determinant, either by loss of one gene copy or loss of gene expression. Further work is required to identify which of the many dozens of SNPs identified in the drug-resistant cell lines contribute to the overall resistance phenotype.
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