1. Biochemistry and Chemical Biology
  2. Microbiology and Infectious Disease
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Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens

  1. Katherine Amberg-Johnson
  2. Sanjay B Hari
  3. Suresh M Ganesan
  4. Hernan A Lorenzi
  5. Robert T Sauer
  6. Jacquin C Niles
  7. Ellen Yeh  Is a corresponding author
  1. Stanford Medical School, United States
  2. Massachusetts Institute of Technology, United States
  3. The J. Craig Venter Institute, United States
Research Article
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Cite this article as: eLife 2017;6:e29865 doi: 10.7554/eLife.29865

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.

Article and author information

Author details

  1. Katherine Amberg-Johnson

    Department of Biochemistry, Stanford Medical School, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sanjay B Hari

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Suresh M Ganesan

    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hernan A Lorenzi

    Department of Infectious Disease, The J. Craig Venter Institute, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Robert T Sauer

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jacquin C Niles

    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ellen Yeh

    Department of Biochemistry, Stanford Medical School, Stanford, United States
    For correspondence
    ellenyeh@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3974-3816

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.

Reviewing Editor

  1. Jon Clardy, Harvard Medical School, United States

Publication history

  1. Received: June 23, 2017
  2. Accepted: August 17, 2017
  3. Accepted Manuscript published: August 18, 2017 (version 1)
  4. Version of Record published: August 30, 2017 (version 2)

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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