In this revised application the Principal Investigator proposes to determine the mode of action of atovaquone, an effective agent in the treatment of Pneumocystis carinii pneumonia. The Investigators and his coworkers have found that P. carinii mitochondria are much less sensitive to atovaquone than the mitochondria from malaria parasites. This suggests that atovaquone might have a different mode of action against P. carinii. Alternately, it suggests that atovaquone is not highly specific for P. carinii mitochondria and that other naphthoquinones with greater specificity might exist.
The specific aims of the project are to: (1) characterize P. carinii mitochondria and determine how they are affected by atovaquone; (2) determine whether therapeutically relevant concentrations of atovaquone inhibit pyrimidine biosynthesis in P. carinii, as in malaria parasites, or cause energy depletion; (3) screen a series of related naphthoquinones as inhibitors of P. carinii respiratory activity; (4) optimize the in vitro culture system and use it to screen these naphthoquinones for antipneumocystis activity; and (5) test the most effective naphthoquinones for antipneumocystis activity in mice. A better understanding of the mode of action of atovaquone could aid in the development of new hydroxynaphthoquinone antipneumocystis agents.
| Walker, D J; Wakefield, A E; Dohn, M N et al. (1998) Sequence polymorphisms in the Pneumocystis carinii cytochrome b gene and their association with atovaquone prophylaxis failure. J Infect Dis 178:1767-75 |
