期刊
ELIFE
卷 6, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.29865
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资金
- National Institutes of Health [1K08AI097239, 1DP5OD012119, U19AI110819, 1DP2OD007124, P50 GM098792, AI016892, F32GM116241, T32GM007276]
- Burroughs Wellcome Fund
- Bill and Melinda Gates Foundation [OPP1069759]
- Stanford Bio-X SIGF William and Lynda Steere Fellowship
- Bill and Melinda Gates Foundation [OPP1069759] Funding Source: Bill and Melinda Gates Foundation
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.
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