Rapid kill of malaria parasites by artemisinin and semi-synthetic endoperoxides involves ROS-dependent depolarization of the membrane potential.
Rapid kill of malaria parasites by artemisinin and semi-synthetic endoperoxides involves ROS-dependent depolarization of the membrane potential.
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DOI：
10.1093/jac/dkt486
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Biagini GA
中科院分区：
文献类型：
--
作者：
Antoine T;Fisher N;Amewu R;O'Neill PM;Ward SA;Biagini GA
青蒿素和青蒿素半合成衍生物（统称为内过氧化物）是治疗无并发症和严重疟疾的一线抗疟药。内过氧化物显示出非常快的杀灭率，并且通常对寄生虫抗性的发展是不利的。这些关键药效学特征是复杂作用机制的结果，其细节缺乏共识。在这里，我们报告的主要生理事件导致寄生虫死亡。在暴露于高相关浓度的内过氧化物（青蒿素、双氢青蒿素、青蒿琥酯和合成的四氧六环RKA 182）后，使用实时单细胞成像测量寄生虫线粒体（Δ Δ Cm）和质膜（Δ Δ Vp）电化学电位。此外，线粒体电子传递链组件NADH：醌氧化还原酶（替代复合物I），BC 1（复合物III）和细胞色素氧化酶（复合物IV）进行了研究，以确定其功能的各种内过氧化物的敏感性。寄生虫暴露于内过氧化物导致寄生虫Δ Δ m和Δ Δ p的快速去极化。去极化率的活性氧（ROS）清除剂和Fe 3+螯合剂的存在下降低。由于直接测定时缺乏显著抑制作用，因此认为内过氧化物对Δ λ m的去极化不是通过抑制线粒体电子传递链组分实现的。研究表明，Δ β m和Δ β p的去极化是通过ROS的产生介导的，ROS的产生是由铁生物激活内过氧化物和/或由铁依赖性氧化应激催化引发的。这些数据进行了讨论的背景下，目前的假设有关的内过氧化物的作用方式。
Artemisinin and artemisinin semi-synthetic derivatives (collectively known as endoperoxides) are first-line antimalarials for the treatment of uncomplicated and severe malaria. Endoperoxides display very fast killing rates and are generally recalcitrant to parasite resistance development. These key pharmacodynamic features are a result of a complex mechanism of action, the details of which lack consensus. Here, we report on the primary physiological events leading to parasite death. Parasite mitochondrial (ΔΨm) and plasma membrane (ΔΨp) electrochemical potentials were measured using real-time single-cell imaging following exposure to pharmacologically relevant concentrations of endoperoxides (artemisinin, dihydroartemisinin, artesunate and the synthetic tetraoxane RKA182). In addition, mitochondrial electron transport chain components NADH:quinone oxidoreductase (alternative complex I), bc1 (complex III) and cytochrome oxidase (complex IV) were investigated to determine their functional sensitivity to the various endoperoxides. Parasite exposure to endoperoxides resulted in rapid depolarization of parasite ΔΨm and ΔΨp. The rate of depolarization was decreased in the presence of a reactive oxygen species (ROS) scavenger and Fe3+ chelators. Depolarization of ΔΨm by endoperoxides is not believed to be through the inhibition of mitochondrial electron transport chain components, owing to the lack of significant inhibition when assayed directly. The depolarization of ΔΨm and ΔΨp is shown to be mediated via the generation of ROS that are initiated by iron bioactivation of endoperoxides and/or catalysed by iron-dependent oxidative stress. These data are discussed in the context of current hypotheses concerning the mode of action of endoperoxides.
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DOI：
10.1074/jbc.m111.324319
发表时间：
2012-03-23
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Fisher N;Abd Majid R;Antoine T;Al-Helal M;Warman AJ;Johnson DJ;Lawrenson AS;Ranson H;O'Neill PM;Ward SA;Biagini GA
通讯作者：
Biagini GA
影响因子：
4.8
作者：
Bhisutthibhan, J;Pan, XQ;Meshnick, SR
通讯作者：
Meshnick, SR
影响因子：
64.8
作者：
Eckstein-Ludwig, U;Webb, RJ;Krishna, S
通讯作者：
Krishna, S
影响因子：
1.5
作者：
HONG, YL;YANG, YZ;MESHNICK, SR
通讯作者：
MESHNICK, SR
影响因子：
4.8
作者：
Fisher, N;Castleden, CK;Meunier, B
通讯作者：
Meunier, B