DB75, a novel trypanocidal agent, disrupts mitochondrial function in Saccharomyces cerevisiae.

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.
AuthorsCharlotte A Lanteri, Bernard L Trumpower, Richard R Tidwell, Steven R Meshnick
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 48 Issue 10 Pg. 3968-74 (Oct 2004) ISSN: 0066-4804 [Print] United States
PMID15388460 (Publication Type: Journal Article)
Chemical References
  • Antifungal Agents
  • Benzamidines
  • Culture Media
  • Trypanocidal Agents
  • Pentamidine
  • furamidine
  • Glycerol
  • Antifungal Agents (pharmacology)
  • Benzamidines (pharmacology)
  • Culture Media
  • Glycerol (metabolism)
  • Intracellular Membranes (drug effects)
  • Membrane Potentials (drug effects)
  • Microscopy, Fluorescence
  • Mitochondria (drug effects, metabolism)
  • Oxygen Consumption (drug effects)
  • Pentamidine (pharmacology)
  • Saccharomyces cerevisiae (drug effects, metabolism)
  • Trypanocidal Agents (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: