We report detailed susceptibility profiling of asexual blood stages of the malaria parasite Plasmodium falciparum to clinical and experimental antimalarials, combined with metabolomic fingerprinting. Results revealed a variety of stage-specific and metabolic profiles that differentiated the modes of action of clinical antimalarials including chloroquine, piperaquine, lumefantrine, and mefloquine, and identified late trophozoite-specific peak activity and stage-specific biphasic dose-responses for the mitochondrial inhibitors DSM265 and atovaquone. We also identified experimental antimalarials hitting previously unexplored druggable pathways as reflected by their unique stage specificity and/or metabolic profiles. These included several ring-active compounds, ones affecting hemoglobin catabolism through distinct pathways, and mitochondrial inhibitors with lower propensities for resistance than either DSM265 or atovaquone. This approach, also applicable to other microbes that undergo multiple differentiation steps, provides an effective tool to prioritize compounds for further development within the context of combination therapies.

中文翻译：

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结合阶段特异性和代谢组学谱分析来推进抗疟药物的发现。

我们报告了疟疾寄生虫恶性疟原虫对临床和实验抗疟疾，结合代谢组学指纹图谱的无性血液阶段的详细敏感性分析。结果显示了各种阶段特异性和代谢特征，这些特征区分了临床抗疟药的作用方式，包括氯喹，哌喹，lumefantrine和甲氟喹，并鉴定了线粒体抑制剂的晚滋养体特异性峰值活性和阶段特异性双相剂量反应。 DSM265和atovaquone。我们还确定了实验性抗疟药击中了以前未曾探索过的可药物化途径，这通过其独特的阶段特异性和/或代谢特征得以反映。其中包括几种具有环活性的化合物，它们通过不同的途径影响血红蛋白的分解代谢，和线粒体抑制剂相比DSM265或atovaquone具有更低的耐药性。这种方法也适用于经历多个分化步骤的其他微生物，提供了一种有效的工具，可以在组合疗法的背景下确定化合物的优先级以进行进一步开发。