Louise M Hughes, C. Lanteri, M. O’Neil
May 1, 2011
Citations
1
Influential Citations
47
Citations
Journal
Molecular and biochemical parasitology
Abstract
Atovaquone is a hydroxy-naphthoquinone that is used to treat parasitic and fungal infections including Plasmodium falciparum (malaria), Pneumocystis jivorecii (pneumonia) and Toxoplasma gondii (toxoplasmosis). It blocks mitochondrial oxidation of ubiquinol in these organisms by binding to the ubiquinol oxidation site of the cytochrome bc(1) complex. Failure of atovaquone treatment has been linked to the appearance of mutations in the mitochondrially encoded gene for cytochrome b. In order to determine the optimal parameters required for inhibition of respiration in parasites and pathogenic fungi and overcome drug resistance, we have synthesized and tested the inhibitory activity of novel hydroxy-naphthoquinones against blood stage P. falciparum and liver stage P. berghei and against cytochrome bc(1) complexes isolated from yeast strains bearing mutations in cytochrome b associated with resistance in Plasmodium, Pneumocystis, and Toxoplasma. One of the new inhibitors is highly effective against an atovaquone resistant Plasmodium and illustrates the type of modification to the hydroxy-naphthoquinone ring of atovaquone that might mitigate drug resistance.