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...
| الحاوية / القاعدة: | eLife |
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| المؤلفون الرئيسيون: | , , , |
| التنسيق: | مقال |
| اللغة: | الإنجليزية |
| منشور في: |
eLife Sciences Publications Ltd
2020-07-01
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| الموضوعات: | |
| الوصول للمادة أونلاين: | https://elifesciences.org/articles/58629 |
| _version_ | 1852690116227629056 |
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| author | Christopher D Goodman Taher Uddin Natalie J Spillman Geoffrey I McFadden |
| author_facet | Christopher D Goodman Taher Uddin Natalie J Spillman Geoffrey I McFadden |
| author_sort | Christopher D Goodman |
| collection | DOAJ |
| container_title | eLife |
| 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. |
| format | Article |
| id | doaj-art-d24db42376c24f489aa9dfd3a0be2dc2 |
| institution | Directory of Open Access Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2020-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| spelling | doaj-art-d24db42376c24f489aa9dfd3a0be2dc22025-08-19T21:24:54ZengeLife Sciences Publications LtdeLife2050-084X2020-07-01910.7554/eLife.58629A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistanceChristopher D Goodman0https://orcid.org/0000-0002-8923-7594Taher Uddin1Natalie J Spillman2Geoffrey I McFadden3School of BioSciences, University of Melbourne, Parkville, AustraliaSchool of BioSciences, University of Melbourne, Parkville, AustraliaSchool of BioSciences, University of Melbourne, Parkville, AustraliaSchool of BioSciences, University of Melbourne, Parkville, AustraliaThe 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.https://elifesciences.org/articles/58629actinoninFTSH1resistanceapicoplast |
| spellingShingle | Christopher D Goodman Taher Uddin Natalie J Spillman Geoffrey I McFadden A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance actinonin FTSH1 resistance apicoplast |
| 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 | actinonin FTSH1 resistance apicoplast |
| url | https://elifesciences.org/articles/58629 |
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