TY - JOUR T1 - A first-in-class inhibitor of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens JF - bioRxiv DO - 10.1101/108910 SP - 108910 AU - Katherine Amberg-Johnson AU - Sanjay B. Hari AU - Suresh M. Ganesan AU - Hernan A. Lorenzi AU - Robert T. Sauer AU - Jacquin C. Niles AU - Ellen Yeh Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/04/108910.abstract N2 - 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. ER -