Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum
Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum
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DOI：
10.1128/aac.01881-12
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发表时间：
2013-03-01
影响因子：
4.9
通讯作者：
Beeson, James G.
中科院分区：
文献类型：
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作者：
Wilson, Danny W.;Langer, Christine;Beeson, James G.
目前用于治疗临床恶性疟原虫疟疾的大多数抗疟药分为两大类，靶向滋养体阶段的食物泡。没有抗疟药显示出针对血液期疟疾的短暂细胞外裂殖子形式。我们使用高通量流式细胞术和研究裂殖子入侵和早期红细胞内发育的新方法研究了一组12种药物（其中10种已在临床上广泛使用）的入侵、裂殖体破裂和生长抑制活性。毫不奇怪，鉴于报道的作用机制，没有一种药物在体外抑制裂殖子入侵。用药物预处理红细胞表明，卤泛群、苯芴群、哌喹、阿莫地喹和甲氟喹扩散进入并保留在红细胞内，并抑制寄生虫的下游生长。研究药物对红细胞内发育、树突破裂和再侵袭的抑制活性，可以确定几种不同的抑制表型。所有药物抑制寄生虫复制时，在环阶段，但只有青蒿琥酯，青蒿素，放线菌酮，和阿司他丁A似乎有实质性的活动，对环阶段，而其他药物的作用后，在红细胞内的发展。当药物被添加到晚期子宫内膜时，只有青蒿素、放线菌酮和曲马斯他丁A能够抑制破裂和随后的复制。流式细胞术被证明是有价值的抗疟活性的体外测定，与自由裂殖子人口作为一个明确的标志物，寄生虫生长抑制。这些研究对于进一步了解抗疟药物的作用机制、研究和评估耐药性以及开发新的抗疟药物具有重要意义。
Most current antimalarials for treatment of clinical Plasmodium falciparum malaria fall into two broad drug families and target the food vacuole of the trophozoite stage. No antimalarials have been shown to target the brief extracellular merozoite form of blood-stage malaria. We studied a panel of 12 drugs, 10 of which have been used extensively clinically, for their invasion, schizont rupture, and growth-inhibitory activity using high-throughput flow cytometry and new approaches for the study of merozoite invasion and early intraerythrocytic development. Not surprisingly, given reported mechanisms of action, none of the drugs inhibited merozoite invasion in vitro. Pretreatment of erythrocytes with drugs suggested that halofantrine, lumefantrine, piperaquine, amodiaquine, and mefloquine diffuse into and remain within the erythrocyte and inhibit downstream growth of parasites. Studying the inhibitory activity of the drugs on intraerythrocytic development, schizont rupture, and reinvasion enabled several different inhibitory phenotypes to be defined. All drugs inhibited parasite replication when added at ring stages, but only artesunate, artemisinin, cycloheximide, and trichostatin A appeared to have substantial activity against ring stages, whereas the other drugs acted later during intraerythrocytic development. When drugs were added to late schizonts, only artemisinin, cycloheximide, and trichostatin A were able to inhibit rupture and subsequent replication. Flow cytometry proved valuable for in vitro assays of antimalarial activity, with the free merozoite population acting as a clear marker for parasite growth inhibition. These studies have important implications for further understanding the mechanisms of action of antimalarials, studying and evaluating drug resistance, and developing new antimalarials.