The interaction of atovaquone with the p. carinii cytochrome bc1 complex.

Author(s): Trumpower, B. | Abstract: Atovaquone is an important second-line therapeutic and prophylactic agent for Pneumocystis carinii pneumonia although it was originally developed as an antimalarial [11]. For malaria, atovaquone is now only used in combination with proguanil, another antimalarial. This combination (Malaronel) is used because atovaquone monotherapy leads to resistance [9]. Atovaquone is structurally similar to ubiquinone (CoQ). UHDBT and stigmatellin are other CoQ analogs that have been well studied in experimental systems. Both UHDBT and stigmatellin are known to inhibit electron transport by binding to the Q0 site of the cytochrome bc1 complex. Atovaquone probably acts at the same site, since it has also been shown to inhibit electron transport in both malaria and P. carinii [4, 6]. This mechanism could also explain the rapid emergence of resistance to monotherapy; mutations could arise easily in cytochrome b, since it is encoded in the mitochondrial genome where the spontaneous mutation rate is 10x higher than in nucleus [1].