Decision letter: A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance [peer_review]

Jon Clardy, Sean Prigge, Ellen Yeh, Gisela Storz, Jon Clardy
2020 unpublished
The antibiotic actinonin kills malaria parasites (Plasmodium falciparum) by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like posttranslational 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
more » ... a 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.
doi:10.7554/elife.58629.sa1 fatcat:c464mtwjuna6lje2vmu2nysala