ArticleAntimicrobial agents and chemotherapy2008
The mitochondrion is a site of trypanocidal action of the aromatic diamidine DB75 in bloodstream forms of Trypanosoma brucei.
Article in Antimicrobial agents and chemotherapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 79 citations in OpenAlex.
- Phase I/II evaluation of the prophylactic antimalarial activity of pafuramidine in healthy volunteers challenged with Plasmodium falciparum sporozoites.The American journal of tropical medicine and hygiene · 2009Trial
- Pathogenic Significance of Trypanosomatids: Progress in Drug Resistance, Control Strategies, and Artificial Intelligence.Interdisciplinary perspectives on infectious diseases · 2026Review
- Sustainable Antiparasitic Agents from an Agro-Industrial Waste: Mitochondria-Targeting Cashew Nutshell Liquid-Derived Phosphonium and Ammonium Salts.Journal of medicinal chemistry · 2025Article
- Uncovering the Unusual Inhibition Mechanism of a Trypanosome Alternative Oxidase Inhibitor Displaying Broad-Spectrum Activity against African Animal Trypanosomes.Journal of medicinal chemistry · 2025Article
- Review
- Mitochondrion of the Trypanosoma brucei long slender bloodstream form is capable of ATP production by substrate-level phosphorylation.PLoS pathogens · 2023Article
- The critical role of mode of action studies in kinetoplastid drug discovery.Frontiers in drug discovery · 2023Article
- Identification of a conserved maxicircle and unique minicircles as part of the mitochondrial genome of Leishmania martiniquensis strain PCM3 in Thailand.Parasites & vectors · 2022Article
- Imidazoline- and Benzamidine-Based Trypanosome Alternative Oxidase Inhibitors: Synthesis and Structure-Activity Relationship Studies.ACS medicinal chemistry letters · 2022Article
- New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story.Tropical medicine and infectious disease · 2020Review
- The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History.Tropical medicine and infectious disease · 2020Review
- Structure-Based Design, Synthesis and Biological Evaluation of Bis-Tetrahydropyran Furan Acetogenin Mimics Targeting the Trypanosomatid F1 Component of ATP Synthase.European journal of organic chemistry · 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
- Insights into antitrypanosomal drug mode-of-action from cytology-based profiling.PLoS neglected tropical diseases · 2018Article
- Review
- Targeting Channels and Transporters in Protozoan Parasite Infections.Frontiers in chemistry · 2018Review
- Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast.Nucleic acids research · 2017Article
- Trypanosoma brucei TbIF1 inhibits the essential F1-ATPase in the infectious form of the parasite.PLoS neglected tropical diseases · 2017Article
- The animal trypanosomiases and their chemotherapy: a review.Parasitology · 2016Review
- Antileishmanial Mechanism of Diamidines Involves Targeting Kinetoplasts.Antimicrobial agents and chemotherapy · 2016Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Human African trypanosomiasis (HAT) is a fatal tropical disease caused by infection with protozoans of the species Trypanosoma brucei gambiense and T. b. rhodesiense. An oral prodrug, DB289, is a promising new therapy undergoing phase III clinical trials for early-stage HAT. DB289 is metabolically converted to the active trypanocidal diamidine DB75 [2,5-bis(4-amidinophenyl)furan]. We previously determined that DB75 inhibits yeast mitochondrial function (C. A. Lanteri, B. L. Trumpower, R. R. Tidwell, and S. R. Meshnick, Antimicrob. Agent Chemother. 48:3968-3974, 2004). The purpose of this study was to investigate if DB75 targets the mitochondrion of T. b. brucei bloodstream forms. DB75 rapidly accumulates within the mitochondria of living trypanosomes, as indicated by the fluorescent colocalization of DB75 with a mitochondrion-specific dye. Fluorescence-activated cell sorting analysis of rhodamine 123-stained living trypanosomes shows that DB75 and other trypanocidal diamidines (pentamidine and diminazene) collapse the mitochondrial membrane potential. DB75 inhibits ATP hydrolysis within T. brucei mitochondria and appears to inhibit the oligomycin-sensitive F 1 F 0-ATPase and perhaps other ATPases. DB75 is most likely not an inhibitor of electron transport within trypanosome mitochondria, since DB75 fails to inhibit mitochondrial respiration when glycerol-3-phosphate is used as the respiratory substrate. However, DB75 inhibits whole-cell respiration (50% inhibitory concentration, 20 microM) at drug concentrations and incubation durations that also result in the dissipation of the mitochondrial membrane potential. Taken together, these findings suggest that the mitochondrion is a target of the trypanocidal action of DB75.
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