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

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 a...

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Autores principales: Goodman, Christopher D, Uddin, Taher, Spillman, Natalie J, McFadden, Geoffrey I
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386903/
https://www.ncbi.nlm.nih.gov/pubmed/32678064
http://dx.doi.org/10.7554/eLife.58629
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author Goodman, Christopher D
Uddin, Taher
Spillman, Natalie J
McFadden, Geoffrey I
author_facet Goodman, Christopher D
Uddin, Taher
Spillman, Natalie J
McFadden, Geoffrey I
author_sort Goodman, Christopher D
collection PubMed
description 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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spelling pubmed-73869032020-07-29 A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance Goodman, Christopher D Uddin, Taher Spillman, Natalie J McFadden, Geoffrey I eLife Cell Biology 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. eLife Sciences Publications, Ltd 2020-07-17 /pmc/articles/PMC7386903/ /pubmed/32678064 http://dx.doi.org/10.7554/eLife.58629 Text en © 2020, Goodman et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Goodman, Christopher D
Uddin, Taher
Spillman, Natalie J
McFadden, Geoffrey I
A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance
title A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance
title_full A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance
title_fullStr A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance
title_full_unstemmed A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance
title_short A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance
title_sort single point mutation in the plasmodium falciparum ftsh1 metalloprotease confers actinonin resistance
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386903/
https://www.ncbi.nlm.nih.gov/pubmed/32678064
http://dx.doi.org/10.7554/eLife.58629
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