1. Biochemistry and Chemical Biology
  2. Microbiology and Infectious Disease

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
https://doi.org/10.7554/eLife.29865
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Cite this article
  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
(2017)
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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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

  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.

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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  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
(2017)
Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens
eLife 6:e29865.
https://doi.org/10.7554/eLife.29865

Share this article

https://doi.org/10.7554/eLife.29865

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Further reading

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    2. Microbiology and Infectious Disease

    A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance

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    The antibiotic actinonin kills malaria parasites (Plasmodium falciparum) by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like post-translational modification in the apicoplast; mimicking its activity against bacteria. However, Amberg Johnson et al. (2017) identified the metalloprotease TgFtsH1 as the target of actinonin in the related parasite Toxoplasma gondii and implicated P. falciparum FtsH1 as a likely target in malaria parasites. The authors were not, however, able to recover actinonin resistant malaria parasites, leaving the specific target of actinonin uncertain. We generated actinonin resistant P. falciparum by in vitro selection and identified a specific sequence change in PfFtsH1 associated with resistance. Introduction of this point mutation using CRISPr-Cas9 allelic replacement was sufficient to confer actinonin resistance in P. falciparum. Our data unequivocally identify PfFtsH1 as the target of actinonin and suggests that actinonin should not be included in the highly valuable collection of ‘irresistible’ drugs for combatting malaria.

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    Disordered proteins interact with the chemical environment to tune their protective function during drying

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    The conformational ensemble and function of intrinsically disordered proteins (IDPs) are sensitive to their solution environment. The inherent malleability of disordered proteins, combined with the exposure of their residues, accounts for this sensitivity. One context in which IDPs play important roles that are concomitant with massive changes to the intracellular environment is during desiccation (extreme drying). The ability of organisms to survive desiccation has long been linked to the accumulation of high levels of cosolutes such as trehalose or sucrose as well as the enrichment of IDPs, such as late embryogenesis abundant (LEA) proteins or cytoplasmic abundant heat-soluble (CAHS) proteins. Despite knowing that IDPs play important roles and are co-enriched alongside endogenous, species-specific cosolutes during desiccation, little is known mechanistically about how IDP-cosolute interactions influence desiccation tolerance. Here, we test the notion that the protective function of desiccation-related IDPs is enhanced through conformational changes induced by endogenous cosolutes. We find that desiccation-related IDPs derived from four different organisms spanning two LEA protein families and the CAHS protein family synergize best with endogenous cosolutes during drying to promote desiccation protection. Yet the structural parameters of protective IDPs do not correlate with synergy for either CAHS or LEA proteins. We further demonstrate that for CAHS, but not LEA proteins, synergy is related to self-assembly and the formation of a gel. Our results suggest that functional synergy between IDPs and endogenous cosolutes is a convergent desiccation protection strategy seen among different IDP families and organisms, yet the mechanisms underlying this synergy differ between IDP families.