Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens
- Stanford Medical School, United States
- Massachusetts Institute of Technology, United States
- The J. Craig Venter Institute, 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.
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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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Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens
eLife 6:e29865.
https://doi.org/10.7554/eLife.29865
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