Suswam E, Kyle D, Lang-Unnasch N
Division of Geographic Medicine, University of Alabama at Birmingham, 1530 South 3rd Avenue, Birmingham, AL 35294-2170, U.S.A.
Exp Parasitol. 2001 Aug;98(4):180-7. doi: 10.1006/expr.2001.4639.
Atovaquone is an antimalarial agent that specifically inhibits the cytochrome bc(1) complex of the cytochrome pathway. High-level atovaquone resistance is associated with a point mutation in the cytochrome b gene. A pair of isogenic clinical isolates of Plasmodium falciparum derived from before and after the acquisition of atovaquone resistance was used to determine whether 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 respiratory 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 inhibitor, salicylhydroxamic acid. Atovaquone appeared to partially inhibit the rate of oxygen consumed through the alternative pathway in only the atovaquone-sensitive isolate. Cross resistance was noted between atovaquone and a new antimalarial agent WR243251. However, the level of WR243251 resistance was very modest compared to the level of atovaquone resistance. WR243251 was shown to rapidly reduce the rate of parasite oxygen consumption by almost 80% in the atovaquone-sensitive isolate and by 57% in the atovaquone-resistant isolate. Drug interaction studies suggest that atovaquone and WR243251 may inhibit growth additively or with mild synergy. Together, these results suggest that while WR243251 may inhibit respiration, its target of action probably differs from that of atovaquone.
阿托伐醌是一种抗疟药，它能特异性抑制细胞色素途径的细胞色素bc(1)复合体。高水平的阿托伐醌耐药性与细胞色素b基因的点突变有关。使用一对源自获得阿托伐醌耐药性前后的恶性疟原虫同基因临床分离株，来确定细胞色素b基因的变化是否导致对阿托伐醌反应时呼吸作用的改变。由于恶性疟原虫似乎利用一个包含细胞色素途径和一条替代呼吸途径的分支呼吸系统，因此研究了敏感和耐药寄生虫利用每条途径的比例。阿托伐醌在敏感分离株中可将寄生虫的总氧消耗量抑制高达66%，但在耐药分离株中仅抑制高达28%。阿托伐醌敏感和耐药的寄生虫对替代途径抑制剂水杨羟肟酸的敏感性相当。阿托伐醌似乎仅在阿托伐醌敏感分离株中部分抑制通过替代途径消耗的氧速率。观察到阿托伐醌与一种新型抗疟药WR243251之间存在交叉耐药性。然而，与阿托伐醌耐药水平相比，WR243251的耐药水平非常低。在阿托伐醌敏感分离株中，WR243251能迅速将寄生虫的氧消耗速率降低近80%，在阿托伐醌耐药分离株中降低57%。药物相互作用研究表明，阿托伐醌和WR243251可能以相加或轻度协同的方式抑制生长。总之，这些结果表明，虽然WR243251可能抑制呼吸作用，但其作用靶点可能与阿托伐醌不同。
