A single point mutation in the < i > Plasmodium falciparum < /i > 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 al. (2017) identified the metalloproteaseTgFtsH1 as the target of actinonin in the related parasiteToxoplasma gondii and implicatedP. falciparumFtsH1 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 resistantP. falciparumbyin vitro selection and identified a specific sequence change inPfFtsH1 associated with resistance. Introduction of this point mutation using CRISPr-Cas9 allelic replacement was sufficient to confer actinonin resistance inP. falciparum. Our data unequivocally identifiesPfFtsH1 as the target of actinonin and suggests that actinonin should not be included in the highly valuable collection of 'irresistible' drugs for combatting malaria.
Source: eLife - Category: Biomedical Science Tags: Cell Biology Microbiology and Infectious Disease Source Type: research