The Mitochondrion Is a Site of Trypanocidal Action of the Aromatic Diamidine DB75 in Bloodstream Forms of Trypanosoma brucei
- 1 March 2008
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 52 (3), 875-882
- https://doi.org/10.1128/aac.00642-07
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 μM) 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.Keywords
This publication has 54 references indexed in Scilit:
- Trypanosoma brucei: Differential requirement of membrane potential for import of proteins into mitochondria in two developmental stagesExperimental Parasitology, 2008
- Diphenyl Furans and Aza Analogs: Effects of Structural Modification on In Vitro Activity, DNA Binding, and Accumulation and Distribution in TrypanosomesAntimicrobial Agents and Chemotherapy, 2007
- Accumulation and Intracellular Distribution of Antitrypanosomal Diamidine Compounds DB75 and DB820 in African TrypanosomesAntimicrobial Agents and Chemotherapy, 2006
- New Approaches to the Microscopic Imaging ofTrypanosoma bruceiMicroscopy and Microanalysis, 2004
- DB75, a Novel Trypanocidal Agent, Disrupts Mitochondrial Function in Saccharomyces cerevisiaeAntimicrobial Agents and Chemotherapy, 2004
- Metabolites of an orally active antimicrobial prodrug, 2,5‐bis(4‐amidinophenyl)furan‐bis‐O‐methylamidoxime, identified by liquid chromatography/tandem mass spectrometryJournal of Mass Spectrometry, 2004
- A thermodynamic and structural analysis of DNA minor-groove complex formationJournal of Molecular Biology, 2000
- Binding of DAPI analog 2,5-bis(4-amidinophenyl)furan to DNABiochemistry, 1993
- Effects of Oligomycin on Glucose Utilization and Calcium Transport in African TrypanosomesMicrobiology, 1980
- Trypanocide Diamidine mit drei isolierten RingsystemenEuropean Journal of Organic Chemistry, 1975