Department of Biochemistry, Stanford Medical School, Stanford, United States.
Microbiology and Immunology, Stanford Medical School, Stanford, United States.
Elife. 2017 Aug 18;6:e29865. doi: 10.7554/eLife.29865.
The malaria parasite and related apicomplexan pathogens contain an essential plastid organelle, the apicoplast, which is a key anti-parasitic target. Derived from secondary endosymbiosis, the apicoplast depends on novel, but largely cryptic, mechanisms for protein/lipid import and organelle inheritance during parasite replication. These critical biogenesis pathways present untapped opportunities to discover new parasite-specific drug targets. We used an innovative screen to identify actinonin as having a novel mechanism-of-action inhibiting apicoplast biogenesis. Resistant mutation, chemical-genetic interaction, and biochemical inhibition demonstrate that the unexpected target of actinonin in and is FtsH1, a homolog of a bacterial membrane AAA+ metalloprotease. FtsH1 is the first novel factor required for apicoplast biogenesis identified in a phenotypic screen. Our findings demonstrate that FtsH1 is a novel and, importantly, druggable antimalarial target. Development of FtsH1 inhibitors will have significant advantages with improved drug kinetics and multistage efficacy against multiple human parasites.
疟原虫和相关的顶复门病原体含有一个必需的质体器官，即顶质体，它是一个关键的抗寄生虫靶点。顶质体来源于二次内共生，它依赖于新颖的，但在很大程度上是隐匿的，蛋白质/脂质输入和细胞器遗传的机制，在寄生虫复制过程中。这些关键的生物发生途径为发现新的寄生虫特异性药物靶点提供了机会。我们使用了一种创新的筛选方法来确定放线菌酮具有抑制顶质体生物发生的新作用机制。抗性突变、化学遗传相互作用和生化抑制表明，放线菌酮在 和 中的意想不到的靶标是 FtsH1，一种细菌膜 AAA+金属蛋白酶的同源物。FtsH1 是在表型筛选中鉴定的第一个新的质体生物发生所必需的因子。我们的研究结果表明，FtsH1 是一个新的、重要的、可成药的抗疟靶点。FtsH1 抑制剂的开发将具有显著的优势，改善药物动力学和多阶段对多种人体寄生虫的疗效。
