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Elife. 2017 Aug 18;6. pii: e29865. doi: 10.7554/eLife.29865.

Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens.

Author information

1
Department of Biochemistry, Stanford Medical School, Stanford, United States.
2
Microbiology and Immunology, Stanford Medical School, Stanford, United States.
3
Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
4
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States.
5
Department of Infectious Disease, The J. Craig Venter Institute, Maryland, United States.
6
Department of Pathology, Stanford Medical School, Stanford, United States.

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 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.

KEYWORDS:

P. falciparum; Toxoplasma gondii; antimalarial; apicoplast; biochemistry; infectious disease; microbiology

PMID:
28826494
PMCID:
PMC5576918
DOI:
10.7554/eLife.29865
[Indexed for MEDLINE]
Free PMC Article

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