1. Cell Biology
  2. Microbiology and Infectious Disease

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

  1. Christopher D Goodman  Is a corresponding author
  2. Taher Uddin
  3. Natalie Jane Spillman
  4. Geoff McFadden
  1. University of Melbourne, Australia
https://doi.org/10.7554/eLife.58629
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  1. Christopher D Goodman
  2. Taher Uddin
  3. Natalie Jane Spillman
  4. Geoff McFadden
(2020)
A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance
eLife 9:e58629.
https://doi.org/10.7554/eLife.58629
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Abstract

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 identifies 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

  1. Christopher D Goodman

    School of BioSciences, University of Melbourne, Parkville, Australia
    For correspondence
    deang@unimelb.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8923-7594

  2. Taher Uddin

    School of BioSciences, University of Melbourne, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.

  3. Natalie Jane Spillman

    School of BioSciences, University of Melbourne, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.

  4. Geoff McFadden

    School of BioSciences, University of Melbourne, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Health and Medical Research Council (Project Grant APP1106213)

  • Christopher D Goodman
  • Geoff McFadden

National Health and Medical Research Council (Project Grant APP1162550)

  • Christopher D Goodman
  • Geoff McFadden

Australian Research Council (Laureate Fellowship FL170100008)

  • Geoff McFadden

National Health and Medical Research Council (CJ Maritn Felowship APP1072217)

  • Natalie Jane Spillman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Goodman 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. Christopher D Goodman
  2. Taher Uddin
  3. Natalie Jane Spillman
  4. Geoff McFadden
(2020)
A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance
eLife 9:e58629.
https://doi.org/10.7554/eLife.58629

Share this article

https://doi.org/10.7554/eLife.58629

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

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