Abstract：
The control and elimination of malaria caused by Plasmodium vivax is hampered by the threat of relapsed infection resulting from the activation of dormant hepatic hypnozoites. Currently, only the 8-aminoquinolines, primaquine and tafenoquine, have been approved for the elimination of hypnozoites, although their use is hampered by potential toxicity. Therefore, an alternative radical curative drug that safely eliminates hypnozoites is a pressing need. This study assessed the potential hypnozoiticidal activity of the antibiotic azithromycin, which is thought to exert antimalarial activity by inhibiting prokaryote-like ribosomal translation within the apicoplast, an indispensable organelle. The results show that azithromycin inhibited apicoplast development during liver-stage schizogony in P. vivax and Plasmodium cynomolgi, leading to impaired parasite maturation. More importantly, this study found that azithromycin is likely to impair the hypnozoite\'s apicoplast, resulting in the loss of this organelle. Subsequently, using a recently developed long-term hepatocyte culture system, this study found that this loss likely induces a delay in the hypnozoite activation rate, and that those parasites that do proceed to schizogony display liver-stage arrest prior to differentiating into hepatic merozoites, thus potentially preventing relapse. Overall, this work provides evidence for the potential use of azithromycin for the radical cure of relapsing malaria, and identifies apicoplast functions as potential drug targets in quiescent hypnozoites.
摘要：
由间日疟原虫引起的疟疾的控制和消除受到由休眠的肝催眠子的激活引起的复发感染的威胁的阻碍。目前,只有8-氨基喹啉,伯氨喹和他非诺喹,已经被批准用于消除催眠，尽管它们的使用受到潜在毒性的阻碍。因此,一种安全地消除催眠的替代治疗药物是一个紧迫的需要。在这项研究中,我们评估了抗生素阿奇霉素的潜在杀催眠活性，它被认为通过抑制原核生物样核糖体翻译来发挥抗疟药活性，在原生质体内，不可或缺的细胞器。我们的结果表明，阿奇霉素在间日疟原虫和食蟹猴肝期分裂过程中抑制了原生质体的发育，导致寄生虫成熟受损。更重要的是,我们发现阿奇霉素很可能会损害被催生子的原生质体，导致该细胞器的丧失。随后，通过使用最近开发的长期肝细胞培养系统，我们发现，这种损失可能会导致一个延迟的催眠体激活率和那些寄生虫，确实进行分裂前显示肝阶段停滞分化为肝裂殖子，因此，有可能预防复发。总之,这项工作为阿奇霉素在复发性疟疾的根治治疗中的潜在用途提供了证据，并确定了在静止的催生子中作为潜在药物靶标的Apicoplast功能。
