ABSTRACT

Chloroquine (CQ) is an important drug used therapeutically for treatment of malaria. However, due to limited number of studies on metabolic targets of chloroquine (CQ), it is difficult to attribute mechanisms underlying resistance associated with usage of this drug. The present study aimed to investigate the metabolic signatures of CQ-resistant Plasmodium falciparum (PfDd2) compared to CQ-sensitive Plasmodium falciparum (Pf3D7). Both Pf3D7 and PfDd2 were treated with CQ at 200 nM for 48 hr; thereafter, the harvested red blood cells (RBCs) and media were subjected to microscopy and high-resolution metabolomics (HRM). Glutathione, γ-L-glutamyl-L-cysteine, spermidine, inosine monophosphate, alanine, and fructose-1,6-bisphosphate were markedly altered in PfDd2 of RBC. In the media, cysteine, cysteic acid, spermidine, phenylacetaldehyde, and phenylacetic acid were significantly altered in PfDd2. These differential metabolic signatures related signaling pathways of PfDd2, such as oxidative stress pathway and glycolysis may provide evidence for understanding the resistance mechanism and pathogenesis of the CQ-resistant parasite.

摘要

氯喹 (CQ) 是一种重要的治疗疟疾药物。然而，由于对氯喹 (CQ) 代谢靶点的研究数量有限，很难确定与使用该药物相关的耐药机制。本研究旨在研究抗 CQ恶性疟原虫(PfDd2) 与 CQ 敏感性恶性疟原虫的代谢特征(Pf3D7)。Pf3D7 和 PfDd2 均用 200 nM 的 CQ 处理 48 小时；此后，对收获的红细胞 (RBC) 和培养基进行显微镜检查和高分辨率代谢组学 (HRM)。红细胞 PfDd2 中的谷胱甘肽、γ-L-谷氨酰-L-半胱氨酸、亚精胺、肌苷单磷酸、丙氨酸和 1,6-二磷酸果糖显着改变。在培养基中，半胱氨酸、半胱氨酸、亚精胺、苯乙醛和苯乙酸在 PfDd2 中显着改变。这些与 PfDd2 信号通路相关的差异代谢特征，如氧化应激通路和糖酵解，可能为理解 CQ 抗性寄生虫的抗性机制和发病机制提供证据。