Plasmodium falciparum: multifaceted resistance to artemisinins

Abstract

Plasmodium falciparum resistance to artemisinins, the most potent and fastest acting anti-malarials, threatens malaria elimination strategies. Artemisinin resistance is due to mutation of the PfK13 propeller domain and involves an unconventional mechanism based on a quiescence state leading to parasite recrudescence as soon as drug pressure is removed. The enhanced P. falciparum quiescence capacity of artemisinin-resistant parasites results from an increased ability to manage oxidative damage and an altered cell cycle gene regulation within a complex network involving the unfolded protein response, the PI3K/PI3P/AKT pathway, the PfPK4/eIF2α cascade and yet unidentified transcription factor(s), with minimal energetic requirements and fatty acid metabolism maintained in the mitochondrion and apicoplast. The detailed study of these mechanisms offers a way forward for identifying future intervention targets to fend off established artemisinin resistance.

Fig. 1

The Keap1 complex in human cells and a hypothetical PfK13 complex

Fig. 2

Mechanism proposed for PfK13-mediated resistance to artemisinins in K13 mutated Plasmodium falciparum at young ring stage. K13-propeller mutation prevents the fixation of uTF and PI3K to the Kelch domain and their ubiquitination, leading to enhanced concentration of PI3P. The artemisinin-induced oxidative stress is responsible for the accumulation of misfolded proteins in the ER endoplasmic reticulum. Misfolded proteins bind to BiP, the complex BiP-PfPK4 is dissociated and PfPK4 phosphorylates uTF and elF2α. elF2α phosphorylation should allow the translocation of uTF in the nucleus to regulate UPR targets and cytoprotective gene expression and also inhibit protein synthesis [75]. BiP immunoglobulin-binding protein, BTB broad-complex, tramtrack and Bric a Brac, CYPB cyclophilin B, eIF2α eukaryotic translation initiation factor 2α, ERC endoplasmic reticulum resident calcium binding protein, PfPK4 P. falciparum protein kinase 4, PI3K phosphatidylinositol 3 kinase, PI3P phosphatidylinositol 3 phosphate, uTF unidentified transcription factor(s)

Fig. 3

Bip-PERK-eIF2α pathway

Fig. 4

Synthetic model of Plasmodium quiescence metabolism. Quiescent P. falciparum parasites demonstrated an arrested glycolysis pathway leading to suspended production of ATP and phosphoenolpyruvate. Basal metabolism is maintained in quiescent parasites due to FASII metabolism in the apicoplast coupled with ATP production in the mitochondrion. Haloxifob, triclosan and atovaquone can disrupt these biochemical pathways [49, 95]. Green protein/enzyme with maintained expression in quiescent rings [49]. ACC acetyl-CoA carboxylase, ACO aconitase, BCKDH branched-chain keto acid dehydratase, coxii cytochrome c sub-unit II, CS citrate synthase, FabI enoyl-ACP reductase, FabZ β-hydroxyacyl-ACP dehydratase, FabG β-ketoacyl-ACP reductase, FabB/F β-ketoacyl-ACP synthase I/II, FabH β-ketoacyl-ACP synthase III, FabD malonyl-CoA:ACP transacylase, FASII fatty acid synthesis type II, FH fumarate hydratase, IDH isocitrate dehydrogenase, KDH α-ketoglutarate dehydrogenase, LDH lactate dehydrogenase, LipA lipoic acid synthase, LipB octanoyl-ACP protein transferase, MQO malate quinone oxidoreductase, ndh2 NADH-ubiquinone oxidoreductase II, PEP phosphoenolpyruvate, PEPCase PEP carboxylase, PEPCK PEP carboxykinase, PDH pyruvate dehydrogenase, PYK pyruvate kinase, SCS succinyl-CoA synthase, SDH succinate dehydrogenase, sdha flavoprotein subunit of succinate dehydrogenase, TCA Tri carboxylic acid, uqcr iron sulfur sub-unit of ubiquinol Cytochrome c reductase [49, 83, 95]