Murphy A D, Lang-Unnasch N
Department of Medicine, University of Alabama at Birmingham 35294-2170, USA.
Antimicrob Agents Chemother. 1999 Mar;43(3):651-4. doi: 10.1128/AAC.43.3.651.
Recent evidence suggests that the malaria parasite Plasmodium falciparum utilizes a branched respiratory pathway including both a cytochrome chain and an alternative oxidase. This branched respiratory pathway model has been used as a basis for examining the mechanism of action of two antimalarial agents, atovaquone and proguanil. In polarographic assays, atovaquone immediately reduced the parasite oxygen consumption rate in a concentration-dependent manner. This is consistent with its previously described role as an inhibitor of the cytochrome bc1 complex. Atovaquone maximally inhibited the rate of P. falciparum oxygen consumption by 73% +/- 10%. At all atovaquone concentrations tested, the addition of the alternative oxidase inhibitor, salicylhydroxamic acid, resulted in a further decrease in the rate of parasite oxygen consumption. At the highest concentrations of atovaquone tested, the activities of salicylhydroxamic acid and atovaquone appear to overlap, suggesting that at these concentrations, atovaquone partially inhibits the alternative oxidase as well as the cytochrome chain. Drug interaction studies with atovaquone and salicylhydroxamic acid indicate atovaquone's activity against P. falciparum in vitro is potentiated by this alternative oxidase inhibitor, with a sum fractional inhibitory concentration of 0.6. Propyl gallate, another alternative oxidase inhibitor, also potentiated atovaquone's activity, with a sum fractional inhibitory concentration of 0.7. Proguanil, which potentiates atovaquone activity in vitro and in vivo, had a small effect on parasite oxygen consumption in polarographic assays when used alone or in the presence of atovaquone or salicylhydroxamic acid. This suggests that proguanil does not potentiate atovaquone by direct inhibition of either branch of the parasite respiratory chain.
最近的证据表明，疟原虫恶性疟原虫利用一种分支呼吸途径，该途径包括细胞色素链和交替氧化酶。这种分支呼吸途径模型已被用作研究两种抗疟药物阿托伐醌和氯胍作用机制的基础。在极谱分析中，阿托伐醌以浓度依赖的方式立即降低了寄生虫的氧消耗率。这与其先前描述的作为细胞色素bc1复合物抑制剂的作用一致。阿托伐醌最大程度地抑制恶性疟原虫的氧消耗率达73%±10%。在所有测试的阿托伐醌浓度下，添加交替氧化酶抑制剂水杨羟肟酸会导致寄生虫氧消耗率进一步降低。在测试的最高阿托伐醌浓度下，水杨羟肟酸和阿托伐醌的活性似乎重叠，这表明在这些浓度下，阿托伐醌不仅部分抑制细胞色素链，还部分抑制交替氧化酶。阿托伐醌与水杨羟肟酸的药物相互作用研究表明，这种交替氧化酶抑制剂可增强阿托伐醌在体外对恶性疟原虫的活性，联合半数抑制浓度为0.6。另一种交替氧化酶抑制剂没食子酸丙酯也增强了阿托伐醌的活性，联合半数抑制浓度为0.7。氯胍在体外和体内均可增强阿托伐醌的活性，但在极谱分析中，单独使用或与阿托伐醌或水杨羟肟酸同时使用时，对寄生虫的氧消耗影响较小。这表明氯胍不是通过直接抑制寄生虫呼吸链的任何一个分支来增强阿托伐醌的活性。
