Metabolic Dysregulation Induced in Plasmodium falciparum by Dihydroartemisinin and Other Front-Line Antimalarial Drugs
Metabolic Dysregulation Induced in Plasmodium falciparum by Dihydroartemisinin and Other Front-Line Antimalarial Drugs
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DOI：
10.1093/infdis/jiv372
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发表时间：
2016-01-15
影响因子：
6.4
通讯作者：
McConville, Malcolm J.
中科院分区：
文献类型：
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作者：
Cobbold, Simon A.;Chua, Hwa H.;McConville, Malcolm J.
有关抗疟疾药物作用模式的详细信息可用于改进现有药物，确定新的药物靶点，并了解耐药性的基础。在这项研究中，我们描述了一种基于时间分辨的、基于质谱学(MS)的代谢物图谱方法来描绘一组临床抗疟疾药物和抑制剂对恶性疟原虫无性血液阶段的代谢扰动。用气相色谱-质谱仪和液相色谱-质谱仪监测恶性疟原虫感染红细胞中药物诱导的代谢物水平随时间的变化，并通过非平稳的[C-13]-葡萄糖标记证实特定代谢通量的变化。双氢青蒿素(DHA)被发现在暴露后1小时内扰乱血红蛋白的分解代谢，导致血红蛋白衍生多肽的一过性下降。出乎意料的是，它还扰乱了嘧啶的生物合成，导致[C-13]-葡萄糖流向苹果酸的产生增加，这可能解释了恶性疟原虫在血液发育早期对DHA的敏感性。阿托瓦酮、氯喹、普罗瓜尼、环瓜尼和亚甲基蓝也有独特的代谢特征。我们还表明，这种方法可以用来确定新的抗疟疾药物的作用模式，如化合物Torin2，它抑制血红蛋白分解代谢。
Detailed information on the mode of action of antimalarial drugs can be used to improve existing drugs, identify new drug targets, and understand the basis of drug resistance. In this study we describe the use of a time-resolved, mass spectrometry ( MS)-based metabolite profiling approach to map the metabolic perturbations induced by a panel of clinical antimalarial drugs and inhibitors on Plasmodium falciparum asexual blood stages. Drug-induced changes in metabolite levels in P. falciparum-infected erythrocytes were monitored over time using gas chromatography-MS and liquid chromatography-MS and changes in specific metabolic fluxes confirmed by nonstationary [C-13]-glucose labeling. Dihydroartemisinin ( DHA) was found to disrupt hemoglobin catabolism within 1 hour of exposure, resulting in a transient decrease in hemoglobin-derived peptides. Unexpectedly, it also disrupted pyrimidine biosynthesis, resulting in increased [C-13]-glucose flux toward malate production, potentially explaining the susceptibility of P. falciparum to DHA during early blood-stage development. Unique metabolic signatures were also found for atovaquone, chloroquine, proguanil, cycloguanil and methylene blue. We also show that this approach can be used to identify the mode of action of novel antimalarials, such as the compound Torin 2, which inhibits hemoglobin catabolism.