A first-in-class inhibitor of parasite FtsH disrupts plastid biogenesis in human pathogens
bioRxiv(2017)
摘要
The malaria parasite Plasmodium falciparum and related apicomplexan pathogens contain an essential plastid organelle, the apicoplast, which is a key anti-parasitic target. Apicoplast biogenesis depends on novel, but largely cryptic, mechanisms for protein/lipid import and organelle inheritance during parasite replication. These critical pathways present untapped opportunities to discover new parasite-specific drug targets. We used an innovative screen to identify the natural product actinonin as a first-in-class antimalarial compound inhibiting apicoplast biogenesis. Resistant mutation, chemical-genetic interaction, and biochemical inhibition demonstrate that the unexpected target of actinonin in P. falciparum and Toxoplasma gondii is FtsH1, a homolog of a bacterial membrane AAA+ metalloprotease. PfFtsH1 is the first novel factor required for apicoplast biogenesis identified in an unbiased screen. Our findings demonstrate that FtsH1 is a novel and, importantly, druggable antimalarial target. Development of FtsH1 inhibitors will have significant advantages over existing apicoplast-targeting compounds with improved drug kinetics and multistage efficacy against multiple human parasites.
更多查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要