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

Christopher D Goodman,Geoffrey I McFadden,Taher Uddin,Natalie J Spillman

doi:10.7554/elife.58629

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.

Highlights

Actinonin is an anti-bacterial and anti-parasitic antibiotic derived from streptomycete bacteria (Gordon et al, 1962; Wiesner et al, 2001)
Actinonin targets peptide deformylase (PDF) (Chen et al, 2000), an enzyme involved in prokaryotic post-translational modification and present in the relict plastid of apicomplexan parasites
Parasites with reduced PfFtsH1 expression were more sensitive to actinonin, all of which prompted the interim conclusion that PfFtsH1, rather than PfPDF, might be the target of actinonin and that PfFtsH1 is a potential new antimalarial target (Amberg-Johnson et al, 2017)

Summary

Introduction

Actinonin is an anti-bacterial and anti-parasitic antibiotic derived from streptomycete bacteria (Gordon et al, 1962; Wiesner et al, 2001). They showed that actinonin inhibits recombinantly expressed human malaria parasite FtsH1 (PfFtsH1) in vitro at levels comparable to its antimalarial activity (Amberg-Johnson et al, 2017).

Results

Conclusion