Plasmodium falciparum: The effects of atovaquone resistance on respiration

Atovaquone is an antimalarial agent that specifically inhibits the cytochro me bc(1) complex of the cytochrome pathway. High-level atovaquone resistanc e is associated with a point mutation in the cytochrome b gene. A pair of i sogenic clinical isolates of Plasmodium falciparum derived from before and after the acquisition of atovaquone resistance was used to determine whethe r the change in the cytochrome b gene resulted in changes in respiration in response to atovaquone. Since P. falciparum appears to utilize a branched respiratory system comprising both the cytochrome and an alternative respir atory pathway, the proportion of each pathway utilized by the sensitive and resistant parasites was investigated. Atovaquone inhibited total parasite oxygen consumption by up to 66% in the sensitive isolate but only up to 28% in the resistant isolate. Both the atovaquone-sensitive and the atovaquone -resistant parasites were comparably sensitive to the alternative pathway i nhibitor, salicylhydroxamic acid. Atovaquone appeared to partially inhibit the rate of oxygen consumed through the alternative pathway in only the ato vaquone-sensitive isolate. Cross resistance was noted between atovaquone an d a new antimalarial agent WR243251. However. the level of WR243251 resista nce was very modest compared to the level of atovaquone resistance. WR24325 1 was shown to rapidly reduce the rate of parasite oxygen consumption by al most 80% in the atovaquone-sensitive isolate and by 57% in the atovaquone-r esistant isolate. Drug interaction studies suggest that atovaquone and WR24 3251 may inhibit growth additively or with mild synergy. Together, these re sults suggest that while WR243251 may inhibit respiration, its target of ac tion probably differs from that of atovaquone. (C) 2001 Academic Press.