The Malaria Parasite's Lactate Transporter PfFNT Is the Target of Antiplasmodial Compounds Identified in Whole Cell Phenotypic Screens

In this study the ‘Malaria Box’ chemical library comprising 400 compounds with antiplasmodial activity was screened for compounds that perturb the internal pH of the malaria parasite, Plasmodium falciparum. Fifteen compounds induced an acidification of the parasite cytosol. Two of these did so by inhibiting the parasite’s formate nitrite transporter (PfFNT), which mediates the H+-coupled efflux from the parasite of lactate generated by glycolysis. Both compounds were shown to inhibit lactate transport across the parasite plasma membrane, and the transport of lactate by PfFNT expressed in Xenopus laevis oocytes. PfFNT inhibition caused accumulation of lactate in parasitised erythrocytes, and swelling of both the parasite and parasitised erythrocyte. Long-term exposure of parasites to one of the inhibitors gave rise to resistant parasites with a mutant form of PfFNT that showed reduced inhibitor sensitivity. This study provides the first evidence that PfFNT is a druggable antimalarial target.

本研究针对包含400种具有抗疟原虫活性的「疟疾盒（Malaria Box）」化合物库，开展了可扰动恶性疟原虫（Plasmodium falciparum）内部pH的化合物筛选。最终获得15种可诱导疟原虫胞质酸化的化合物，其中2种通过抑制疟原虫甲酸亚硝酸盐转运蛋白（PfFNT）发挥酸化作用——该蛋白负责介导糖酵解产生的乳酸以H+偶联方式从疟原虫胞内排出。实验证实，这两种化合物均可抑制乳酸跨疟原虫质膜的转运，以及在非洲爪蟾（Xenopus laevis）卵母细胞中表达的PfFNT所介导的乳酸转运过程。PfFNT抑制会导致受疟原虫感染的红细胞内乳酸蓄积，并使疟原虫与受感染红细胞均出现肿胀。将疟原虫长期暴露于其中一种抑制剂后，可分离得到携带PfFNT突变体的抗药性疟原虫，该突变体对该抑制剂的敏感性显著降低。本研究首次提供实验证据，证明PfFNT是一个可成药性抗疟疾药物靶点。