A first-in-class inhibitor of parasite FtsH disrupts plastid biogenesis in human pathogens

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.