A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance
- University of Melbourne, Australia
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.
Article and author information
Author details
Christopher D Goodman
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.
Reviewing Editor
- Jon Clardy, Harvard Medical School, United States
Version history
- Received: May 13, 2020
- Accepted: July 17, 2020
- Accepted Manuscript published: July 17, 2020 (version 1)
- Version of Record published: July 28, 2020 (version 2)
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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A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance
eLife 9:e58629.
https://doi.org/10.7554/eLife.58629
