Department of Biochemistry, Stanford Medical School, Stanford, United States; Microbiology and Immunology, Stanford Medical School, Stanford, United States
Sanjay B Hari
Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
Suresh M Ganesan
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
Hernan A Lorenzi
Department of Infectious Disease, The J. Craig Venter Institute, Maryland, United States
Robert T Sauer
Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
Jacquin C Niles
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
Department of Biochemistry, Stanford Medical School, Stanford, United States; Microbiology and Immunology, Stanford Medical School, Stanford, United States; Department of Pathology, Stanford Medical School, Stanford, United States
The malaria parasite Plasmodium falciparum 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 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 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.
