ArticlePLoS biology2015
Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance.
Article in PLoS biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 187 papers, 2 of them syntheses that pooled it.
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Who cites it
187 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Ubiquitin-proteasome system inFrontiers in medicine · 2024Pooled it
- Pooled it
- Characterisation of the thermal and non-thermal stress conditions that activate the Plasmodium falciparum AP2-HS-dependent heat-shock response.PLoS pathogens · 2026Article
- Anticancer proteasome inhibitors are detrimental to the growth of Toxoplasma gondii in vitro.BMC research notes · 2026Article
- Integrative genomics ofbioRxiv : the preprint server for biology · 2026Article
- Natural triterpenic phenolic esters target PfA-M17 in Plasmodium falciparum.Malaria journal · 2026Article
- Characterization of the Regulatory AAA-ATPase Subunit Rpt3 inInternational journal of molecular sciences · 2025Article
- A review on molecular markers ofJournal of parasitic diseases : official organ of the Indian Society for Parasitology · 2025Review
- Safeguarding artemisinin: integrating bioproduction innovation and resistance management for malaria eradication.Malaria journal · 2025Review
- Antimicrobial activity and possible mechanisms of juglone against Escherichia coli, Staphylococcus aureus, and Salmonella pullorum.BMC microbiology · 2025Article
- A recombinant expression system for thebioRxiv : the preprint server for biology · 2025Article
- Combating Malaria: Targeting the Ubiquitin-Proteasome System to Conquer Drug Resistance.Tropical medicine and infectious disease · 2025Review
- Artemisinin pressure in field isolates can select highly resistantAntimicrobial agents and chemotherapy · 2025Article
- Monitoring molecular markers associated with antimalarial drug resistance in south-east Senegal from 2021 to 2023.The Journal of antimicrobial chemotherapy · 2025Article
- The essential genome ofScience (New York, N.Y.) · 2025Article
- Structural comparison of human and Plasmodium proteasome β5 subunits: informing selective inhibitor design for anti-malaria agents.Malaria journal · 2025Article
- Artemisinin Stimulates Neuronal Cell Viability and Possess a Neuroprotective Effect In Vitro.Molecules (Basel, Switzerland) · 2025Article
- Artemisinin-resistant malaria.Clinical microbiology reviews · 2024Review
- Population genomics and transcriptomics of Plasmodium falciparum in Cambodia and Vietnam uncover key components of the artemisinin resistance genetic background.Nature communications · 2024Article
- A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo.PLoS pathogens · 2024Article
127 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors.
Funding
Abstract
Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs) has emerged, and that the prevalence of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propeller protein. We undertook a detailed kinetic analysis of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin). We demonstrate that ART treatment induces growth retardation and an accumulation of ubiquitinated proteins, indicative of a cellular stress response that engages the ubiquitin/proteasome system. We show that resistant parasites exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. We found that the stress response can be targeted by inhibiting the proteasome. Accordingly, clinically used proteasome inhibitors strongly synergize ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type K13. Synergy is also observed against Plasmodium berghei in vivo. We developed a detailed model of parasite responses that enables us to infer, for the first time, in vivo parasite clearance profiles from in vitro assessments of ART sensitivity. We provide evidence that the clinical marker of resistance (delayed parasite clearance) is an indirect measure of drug efficacy because of the persistence of unviable parasites with unchanged morphology in the circulation, and we suggest alternative approaches for the direct measurement of viability. Our model predicts that extending current three-day ART treatment courses to four days, or splitting the doses, will efficiently clear resistant parasite infections. This work provides a rationale for improving the detection of ART resistance in the field and for treatment strategies that can be employed in areas with ART resistance.
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