Tetracyclines specifically target the picoplast of the malaria parasite Plasmodium falciparum
Tetracyclines specifically target the picoplast of the malaria parasite Plasmodium falciparum
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DOI：
10.1128/aac.00394-06
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发表时间：
2006-09-01
影响因子：
4.9
通讯作者：
Rosenthal, Philip J.
中科院分区：
文献类型：
--
作者：
Dahl, Erica L.;Shock, Jennifer L.;Rosenthal, Philip J.
四环素类是有效但作用缓慢的抗疟药物，其作用机制仍不确定。为了表征四环素类药物的抗疟机制，我们评估了它们在培养的恶性疟原虫中的阶段特异性活性、对寄生虫转录的影响以及对两个预测的细胞器靶点（顶质体和寄生虫）的影响。两个48小时生命周期后的抗疟效果比一个周期后的效果要大得多，即使在第一个周期结束时将药物移除。强力霉素处理的寄生虫在形态上正常，直到第二个治疗周期的后期，但未能发育成裂殖子。强力霉素特异性地损害顶质体基因的表达。顶质体形态最初出现正常的强力霉素的存在下。然而，顶质体异常的后代强力霉素处理的寄生虫，证明了顶质体基因组复制的块，缺乏加工的顶质体靶向蛋白质，并未能延长和隔离在寄生虫。核和线粒体基因组的复制和线粒体形态似乎正常。我们的研究结果表明，四环素特异性地阻断顶质体基因组的表达，导致无功能的顶质体分布到女儿裂殖子中。经治疗的寄生虫的后代中顶质体功能的丧失导致缓慢但有效的抗疟作用。
Tetracyclines are effective but slow-acting antimalarial drugs whose mechanism of action remains uncertain. To characterize the antimalarial mechanism of tetracyclines, we evaluated their stage-specific activities, impacts on parasite transcription, and effects on two predicted organelle targets, the apicoplast and the mitochondrion, in cultured Plasmodium falciparum. Antimalarial effects were much greater after two 48-h life cycles than after one cycle, even if the drugs were removed at the end of the first cycle. Doxycycline-treated parasites appeared morphologically normal until late in the second cycle of treatment but failed to develop into merozoites. Doxycycline specifically impaired the expression of apicoplast genes. Apicoplast morphology initially appeared normal in the presence of doxycycline. However, apicoplasts were abnormal in the progeny of doxycycline-treated parasites, as evidenced by a block in apicoplast genome replication, a lack of processing of an apicoplast-targeted protein, and failure to elongate and segregate during schizogeny. Replication of the nuclear and mitochondrial genomes and mitochondrial morphology appeared normal. Our results demonstrate that tetracyclines specifically block expression of the apicoplast genome, resulting in the distribution of nonfunctional apicoplasts into daughter merozoites. The loss of apicoplast function in the progeny of treated parasites leads to a slow but potent antimalarial effect.