Mode of action of quinoline antimalarial drugs in red blood cells infected by Plasmodium falciparum revealed in vivo
Mode of action of quinoline antimalarial drugs in red blood cells infected by Plasmodium falciparum revealed in vivo
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DOI：
10.1073/pnas.1910123116
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发表时间：
2019-11-12
影响因子：
11.1
通讯作者：
Als-Nielsen, Jens
中科院分区：
文献类型：
--
作者：
Kapishnikov, Sergey;Staalso, Trine;Als-Nielsen, Jens
使用最广泛的抗疟疾药物属于喹啉家族。它们的作用方式在体内还没有在分子水平上得到表征。我们报道了药物氯喹的溴代类似物在快速冷冻的恶性疟原虫感染的红细胞中的作用模式。疟原虫消化血红蛋白，释放出对寄生虫有毒性的副产品--血红素。它通过在寄生的消化液泡中结晶成惰性的血球蛋白来解毒。通过用非破坏性X射线显微镜绘制这种受感染的红细胞图，我们观察到溴喹覆盖了血球蛋白晶体。测得的晶体表面覆盖率足以抑制血球蛋白晶体的进一步生长，从而破坏血红素的解毒作用。此外，我们还发现溴喹在消化液泡中积累，浓度达到亚毫米级，是培养液中药物浓度的1000倍以上。溴喹浓度的如此显著增加提高了药物在阻止血红素对接到血球蛋白晶体表面的效率。根据对溴喹在消化液泡及其膜表面分布的直接观察，我们推测过量的溴喹与剩余的血红素形成了一种络合物，使其失去了结晶。这种复合体被驱使到消化液泡膜，增加了膜穿透和血红素溢出到寄生虫内部的机会。
The most widely used antimalarial drugs belong to the quinoline family. Their mode of action has not been characterized at the molecular level in vivo. We report the in vivo mode of action of a bromo analog of the drug chloroquine in rapidly frozen Plasmodium falciparum-infected red blood cells. The Plasmodium parasite digests hemoglobin, liberating the heme as a byproduct, toxic to the parasite. It is detoxified by crystallization into inert hemozoin within the parasitic digestive vacuole. By mapping such infected red blood cells with nondestructive X-ray microscopy, we observe that bromoquine caps hemozoin crystals. The measured crystal surface coverage is sufficient to inhibit further hemozoin crystal growth, thereby sabotaging heme detoxification. Moreover, we find that bromoquine accumulates in the digestive vacuole, reaching submillimolar concentration, 1,000-fold more than that of the drug in the culture medium. Such a dramatic increase in bromoquine concentration enhances the drug's efficiency in depriving heme from docking onto the hemozoin crystal surface. Based on direct observation of bromoquine distribution in the digestive vacuole and at its membrane surface, we deduce that the excess bromoquine forms a complex with the remaining heme deprived from crystallization. This complex is driven toward the digestive vacuole membrane, increasing the chances of membrane puncture and spillage of heme into the interior of the parasite.