Mitochondria as a Potential Target for the Development of Prophylactic and Therapeutic Drugs against Schistosoma mansoni Infection
Mitochondria as a Potential Target for the Development of Prophylactic and Therapeutic Drugs against Schistosoma mansoni Infection
复制标题
线粒体作为开发曼氏血吸虫感染预防和治疗药物的潜在靶点
DOI：
10.1128/aac.00418-21
复制
发表时间：
2021
影响因子：
4.9
通讯作者：
Hamano Shinjiro
中科院分区：
文献类型：
--
作者：
Talaam Keith Kiplangat;Inaoka Daniel Ken;Hatta Takeshi;Tsubokawa Daigo;Tsuji Naotoshi;Wada Minoru;Saimoto Hiroyuki;Kita Kiyoshi;Hamano Shinjiro
对吡喹酮（唯一的治疗剂）耐药的寄生虫的出现及其作为预防剂的无效性（对迁移/幼年曼氏血吸虫无活性），使得新的抗血吸虫药物的开发变得迫切。寄生虫的细胞器是药物开发的一个有吸引力的目标，因为这种细胞器在寄生虫的整个生命周期中对生存至关重要。我们研究了116种化合物对曼氏血吸虫尾蚴运动的影响，据报道，这些化合物会影响其他生物体中的寄生虫相关过程。接下来，选择八种化合物加两种对照（甲氟喹和吡喹酮），并针对童虫（体外）和成虫（离体）的运动性进行测定。使用感染的小鼠模型进行预防性和治疗性测定。采用Seahorse XFe 24全自动生化分析仪测定细胞耗氧率（OCR）。所有选定的化合物均显示出优异的预防活性，将肺中的虫负荷降低至低于溶媒对照中获得的虫负荷的15%。值得注意的是，子囊呋喃酮显示出最高的活性，蠕虫负荷减少98%，表明子囊呋喃酮作为预防剂的开发潜力。感染小鼠体内的虫负荷较感染前明显降低。在用甲氟喹、硝唑尼特、胺碘酮、Ascofuranone、双羟萘酸pyrvinium或白花丹精处理的小鼠中，成年期的Mansoni减少了50%以上。此外，成人线粒体OCR受到严重抑制的ascofuranone，阿托伐醌，和nitazoxanide，而pyrvinium双羟萘酸抑制线粒体和非线粒体的OCR。这些结果表明，S. mansoni是药物开发的可行目标。
The emergence of parasites resistant to praziquantel, the only therapeutic agent, and its ineffectiveness as a prophylactic agent (inactive against the migratory/juvenile Schistosoma mansoni), make the development of new antischistosomal drugs urgent. The parasite’s mitochondrion is an attractive target for drug development, because this organelle is essential for survival throughout the parasite’s life cycle. We investigated the effects of 116 compounds against Schistosoma mansoni cercaria motility that have been reported to affect mitochondrion-related processes in other organisms. Next, eight compounds plus two controls (mefloquine and praziquantel) were selected and assayed against the motility of schistosomula (in vitro) and adults (ex vivo). Prophylactic and therapeutic assays were performed using infected mouse models. Inhibition of oxygen consumption rate (OCR) was assayed using Seahorse XFe24 analyzer. All selected compounds showed excellent prophylactic activity, reducing the worm burden in the lungs to less than 15% of that obtained in the vehicle control. Notably, ascofuranone showed the highest activity, with a 98% reduction of the worm burden, suggesting the potential for the development of ascofuranone as a prophylactic agent. The worm burden of infected mice with S. mansoni at the adult stage was reduced by more than 50% in mice treated with mefloquine, nitazoxanide, amiodarone, ascofuranone, pyrvinium pamoate, or plumbagin. Moreover, adult mitochondrial OCR was severely inhibited by ascofuranone, atovaquone, and nitazoxanide, while pyrvinium pamoate inhibited both mitochondrial and nonmitochondrial OCRs. These results demonstrate that the mitochondria of S. mansoni are a feasible target for drug development.