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Mechanisms of Action: Physiological Effects

The Mitochondrion Is a Site of Trypanocidal Action of the Aromatic Diamidine DB75 in Bloodstream Forms of Trypanosoma brucei

Charlotte A. Lanteri, Richard R. Tidwell, Steven R. Meshnick
Charlotte A. Lanteri
1Department of Pathology and Laboratory Medicine
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Richard R. Tidwell
1Department of Pathology and Laboratory Medicine
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Steven R. Meshnick
2Departments of Microbiology & Immunology and Epidemiology, University of North Carolina, Chapel Hill, North Carolina
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  • For correspondence: Meshnick@email.unc.edu
DOI: 10.1128/AAC.00642-07
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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 F1F0-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.

  • Copyright © 2008 American Society for Microbiology
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The Mitochondrion Is a Site of Trypanocidal Action of the Aromatic Diamidine DB75 in Bloodstream Forms of Trypanosoma brucei
Charlotte A. Lanteri, Richard R. Tidwell, Steven R. Meshnick
Antimicrobial Agents and Chemotherapy Feb 2008, 52 (3) 875-882; DOI: 10.1128/AAC.00642-07

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The Mitochondrion Is a Site of Trypanocidal Action of the Aromatic Diamidine DB75 in Bloodstream Forms of Trypanosoma brucei
Charlotte A. Lanteri, Richard R. Tidwell, Steven R. Meshnick
Antimicrobial Agents and Chemotherapy Feb 2008, 52 (3) 875-882; DOI: 10.1128/AAC.00642-07
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KEYWORDS

Benzamidines
Blood
mitochondria
Trypanocidal Agents
Trypanosoma brucei brucei

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