Malaria is a pervasive disease that affects millions of lives each year in equatorial regions of the world. During the erythrocytic phase of the parasite life cycle, Plasmodium falciparum invade red blood cells, where they catabolize hemoglobin and sequester the released toxic heme as innocuous hemozoin crystals. Artemisinin-class drugs are activated in vivo by newly-released heme, which creates a carbon-centered radical that markedly reduces parasite density. Radical damage to parasite lipids and proteins is perceived to be artemisinins’ dominant mechanism of action. By contrast, quinoline-class antimalarials inhibit the formation of hemozoin and in this way suppress heme detoxification. Here, we combine malaria parasite assays and scanning probe microscopy of growing beta-hematin crystals to elucidate an unexpected mechanism employed by two widely administered antimalarials, artemisinin and artesunate, to subdue the erythrocytic phase of the parasite life cycle. We demonstrate that heme-drug adducts, produced after the radical activation of artemisinins and largely believed to be benign bystanders, potently kills P. falciparum at low concentrations. We show that these adducts inhibit b-hematin crystallization and heme detoxification, a pathway which complements the deleterious effect of radicals generated via parent drug activation. Our findings reveal an irreversible mechanism of heme-artemisinin adduct inhibition of heme crystallization, unique among antimalarials and common crystal growth inhibitors, that opens new avenues for evaluating drug dosing regimens and understanding growing resistance of P. falciparum to artemisinin.

中文翻译：

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青蒿素抑制恶性疟原虫的第二种机制取决于抑制血红素结晶

疟疾是一种普遍性疾病，每年影响世界赤道地区数百万人的生命。在寄生虫生命周期的红细胞阶段，恶性疟原虫侵入红细胞，在那里分解代谢血红蛋白并将释放的有毒血红素隔离为无害的疟原虫色素晶体。青蒿素类药物在体内被新释放的血红素激活，产生以碳为中心的自由基，显着降低寄生虫密度。对寄生虫脂质和蛋白质的根本性损害被认为是青蒿素的主要作用机制。相比之下，喹啉类抗疟药抑制疟原虫色素的形成，从而抑制血红素解毒。这里，我们将疟疾寄生虫检测和生长的β-血红素晶体的扫描探针显微镜结合起来，阐明了两种广泛使用的抗疟药青蒿素和青蒿琥酯所采用的意想不到的机制，以抑制寄生虫生命周期的红细胞阶段。我们证明，青蒿素彻底激活后产生的血红素药物加合物，在很大程度上被认为是良性旁观者，可以在低浓度下有效杀死恶性疟原虫。我们发现这些加合物抑制β-血红素结晶和血红素解毒，这是一种补充通过母体药物激活产生的自由基的有害作用的途径。我们的研究结果揭示了血红素-青蒿素加合物抑制血红素结晶的不可逆机制，这在抗疟药和常见晶体生长抑制剂中是独一无二的，