Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens
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.
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Author details
Funding
National Institutes of Health (1K08AI097239)
- Ellen Yeh
National Institutes of Health (F32GM116241)
- Sanjay B Hari
National Institutes of Health (T32GM007276)
- Katherine Amberg-Johnson
Burroughs Wellcome Fund
- Ellen Yeh
Bill and Melinda Gates Foundation (OPP1069759)
- Jacquin C Niles
Stanford Bio-X SIGF William and Lynda Steere Fellowship
- Katherine Amberg-Johnson
National Institutes of Health (1DP5OD012119)
- Ellen Yeh
National Institutes of Health (U19AI110819)
- Hernan A Lorenzi
National Institutes of Health (1DP2OD007124)
- Jacquin C Niles
National Institutes of Health (P50 GM098792)
- Jacquin C Niles
National Institutes of Health (AI016892)
- Robert T Sauer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Amberg-Johnson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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