title: DB75, a novel trypanocidal agent, disrupts mitochondrial function in Saccharomyces cerevisiae.
abstract: The aromatic diamidines represent a class of compounds with broad-spectrum antimicrobial activity; however, their development is hindered by a lack of understanding of their mechanism of antimicrobial action. DB75 [2,5-bis(4-amidinophenyl)furan] is a trypanocidal aromatic diamidine that was originally developed as a structural analogue of the antitrypanosomal agent pentamidine. DB289, a novel orally active prodrug of DB75, is undergoing phase IIb clinical trials for early-stage human African trypanosomiasis, Pneumocystis jiroveci carinii pneumonia, and malaria. The purpose of this study was to investigate mechanisms of action of DB75 using Saccharomyces cerevisiae as a model organism. The results of this investigation suggest that DB75 inhibits mitochondrial function. Yeast cells relying upon mitochondrial metabolism for energy production are especially sensitive to DB75. DB75 localizes (by fluorescence) within the mitochondria of living yeast cells and collapses the mitochondrial membrane potential in isolated yeast mitochondria. Furthermore, addition of DB75 to yeast cells or isolated rat liver mitochondria results in immediate uncoupling of oxidative phosphorylation and subsequent inhibition of respiration. We conclude that the mitochondrion is a cellular target of DB75 in yeast cells and anticipate that the results of this study will aid in the target-based design of new antimicrobial aromatic diamidines.
authors.affiliation: Department of Pathology and Laboratory Medicine, Room 805, Brinkhous-Bullitt Building, University of North Carolina, Chapel Hill, NC 27599-7525, USA. Tidwell@med.unc.edu
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Lanteri
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Trumpower
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
authors.forename: Steven R
authors.initials: SR
authors.lastname: Meshnick
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D001550:Benzamidines / Q000494:pharmacology*; D003470:Culture Media; D005990:Glycerol / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010419:Pentamidine / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D001550:Benzamidines; D003470:Culture Media; D014344:Trypanocidal Agents; D010419:Pentamidine; C033286:furamidine; D005990:Glycerol