Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens

Elife. 2017 Aug 18;6:e29865. doi: 10.7554/eLife.29865.

Abstract

The malaria parasite Plasmodium falciparum and related apicomplexan pathogens contain an essential plastid organelle, the apicoplast, which is a key anti-parasitic target. Derived from secondary endosymbiosis, the apicoplast depends on novel, but largely cryptic, mechanisms for protein/lipid import and organelle inheritance during parasite replication. These critical biogenesis pathways present untapped opportunities to discover new parasite-specific drug targets. We used an innovative screen to identify actinonin as having a novel mechanism-of-action inhibiting apicoplast biogenesis. Resistant mutation, chemical-genetic interaction, and biochemical inhibition demonstrate that the unexpected target of actinonin in P. falciparum and Toxoplasma gondii is FtsH1, a homolog of a bacterial membrane AAA+ metalloprotease. PfFtsH1 is the first novel factor required for apicoplast biogenesis identified in a phenotypic screen. Our findings demonstrate that FtsH1 is a novel and, importantly, druggable antimalarial target. Development of FtsH1 inhibitors will have significant advantages with improved drug kinetics and multistage efficacy against multiple human parasites.

Keywords: P. falciparum; Toxoplasma gondii; antimalarial; apicoplast; biochemistry; infectious disease; microbiology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Antimalarials / pharmacology*
  • Apicoplasts / drug effects*
  • Apicoplasts / metabolism
  • Apicoplasts / ultrastructure
  • Drug Repositioning
  • Drug Resistance
  • Erythrocytes / parasitology
  • Fibroblasts / parasitology
  • Gene Expression
  • Gene Knockdown Techniques
  • High-Throughput Screening Assays
  • Humans
  • Hydroxamic Acids / pharmacology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Metalloproteases / antagonists & inhibitors
  • Metalloproteases / deficiency
  • Metalloproteases / genetics*
  • Mutation
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / growth & development
  • Plasmodium falciparum / metabolism
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / deficiency
  • Protein Isoforms / genetics
  • Small Molecule Libraries / pharmacology*
  • Toxoplasma / drug effects*
  • Toxoplasma / genetics
  • Toxoplasma / growth & development
  • Toxoplasma / metabolism

Substances

  • Anti-Bacterial Agents
  • Antimalarials
  • Hydroxamic Acids
  • Membrane Proteins
  • Protein Isoforms
  • Small Molecule Libraries
  • Metalloproteases
  • FtsH1 protein, Toxoplasma gondii
  • actinonin