Effects of Atovaquone and Diospyrin-Based Drugs on Ubiquinone Biosynthesis in Pneumocystis carinii Organisms

Abstract

ABSTRACT The naphthoquinone atovaquone is effective against Plasmodium and Pneumocystis carinii carinii . In Plasmodium , the primary mechanism of drug action is an irreversible binding to the mitochondrial cytochrome bc 1 complex as an analog of ubiquinone. Blockage of the electron transport chain ultimately inhibits de novo pyrimidine biosynthesis since dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis, is unable to transfer electrons to ubiquinone. In the present study, the effect of atovaquone was examined on Pneumocystis carinii carinii coenzyme Q biosynthesis (rather than electron transport and respiration) by measuring its effect on the incorporation of radiolabeled p -hydroxybenzoate into ubiquinone in vitro. A triphasic dose-response was observed, with inhibition at 10 nM and then stimulation up to 0.2 μM, followed by inhibition at 1 μM. Since other naphthoquinone drugs may also act as analogs of ubiquinone, diospyrin and two of its derivatives were also tested for their effects on ubiquinone biosynthesis in P. carinii carinii . In contrast to atovaquone, these drugs did not inhibit the incorporation of p -hydroxybenzoate into P. carinii carinii ubiquinone.