+441518081136Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens
4th International Congress on Drug Discovery, Designing and Development & International Conference and Exhibition on Biochemistry, Molecular Biology: R&D
November 02-03, 2017 Chicago, USA
Katherine Amberg-Johnson
Stanford University, USA
Posters & Accepted Abstracts : J Pharmacol Ther Res
Abstract:
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 parasitespecific 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.
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