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A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance.
Goodman, Christopher D; Uddin, Taher; Spillman, Natalie J; McFadden, Geoffrey I.
Afiliação
  • Goodman CD; School of BioSciences, University of Melbourne, Parkville, Australia.
  • Uddin T; School of BioSciences, University of Melbourne, Parkville, Australia.
  • Spillman NJ; School of BioSciences, University of Melbourne, Parkville, Australia.
  • McFadden GI; School of BioSciences, University of Melbourne, Parkville, Australia.
Elife ; 92020 07 17.
Article em En | MEDLINE | ID: mdl-32678064
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 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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Resistência a Medicamentos / Proteínas de Protozoários / Mutação Puntual / Metaloproteases / Proteínas de Membrana / Antimaláricos Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Resistência a Medicamentos / Proteínas de Protozoários / Mutação Puntual / Metaloproteases / Proteínas de Membrana / Antimaláricos Idioma: En Ano de publicação: 2020 Tipo de documento: Article