Widespread Plasmodium falciparum resistance to first-line antimalarials underscores the vital need to develop compounds with novel modes of action and identify new druggable targets. Here, we profile five compounds that potently inhibit P. falciparum asexual blood stages. Resistance selection studies with three carboxamide-containing compounds, confirmed by gene editing and conditional knockdowns, identify point mutations in the parasite transporter ABCI3 as the primary mediator of resistance. Selection studies with imidazopyridine or quinoline-carboxamide compounds also yield changes in ABCI3, this time through gene amplification. Imidazopyridine mode of action is attributed to inhibition of heme detoxification, as evidenced by cellular accumulation and heme fractionation assays. For the copy-number variation-selecting imidazopyridine and quinoline-carboxamide compounds, we find that resistance, manifesting as a biphasic concentration-response curve, can independently be mediated by mutations in the chloroquine resistance transporter PfCRT. These studies reveal the interconnectedness of P. falciparum transporters in overcoming drug pressure in different parasite strains.

恶性疟原虫对一线抗疟药的广泛耐药性强调了开发具有新作用模式的化合物和确定新的药物靶标的迫切需要。在这里，我们介绍了五种能有效抑制P的化合物。恶性疟原虫无性血液阶段。通过基因编辑和条件性敲低证实的三种含甲酰胺化合物的耐药性选择研究将寄生虫转运蛋白 ABCI3 中的点突变确定为耐药性的主要介质。咪唑并吡啶或喹啉甲酰胺化合物的选择研究也产生了 ABCI3 的变化，这次是通过基因扩增。咪唑并吡啶的作用方式归因于血红素解毒的抑制，细胞积累和血红素分级分析证明了这一点。对于拷贝数变异选择咪唑并吡啶和喹啉甲酰胺化合物，我们发现表现为双相浓度-反应曲线的耐药性可以独立地由氯喹耐药转运蛋白 PfCRT 的突变介导。这些研究揭示了P. _ 恶性疟原虫转运蛋白克服不同寄生虫菌株的药物压力。