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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  Tg FtsH1 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  Pf FtsH1 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  Pf FtsH1 as the target of actinonin and suggests that actinonin should not be included in the highly valuable collection of ‘irresistible’ drugs for combatting malaria.

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