‘Artemisinin Resistance’: Something New or Old? Something of a Misnomer?

Wellems, Thomas E.; Sá, Juliana M.; Su, Xin‐zhuan; Connelly, Sean; Ellis, Angela C

doi:10.1016/j.pt.2020.05.013

Cited by 29 publications

(27 citation statements)

References 80 publications

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“…In Saccharomyces cerevisiae, nuclear gene Nonmitochondrial Citrate Synthase 2 (CIT2) transcription was increased after inhibition of mitochondrial respiration [50], and mitochondrial pathways were activated in response to ER stress [51]. In these studies, mitochondria and the MRR were These responses may relate to an innate growth bistability phenomenon whereby a fraction of the drug-exposed population switches into the metabolic quiescence of persister forms, as we have discussed elsewhere [53].…”

Section: Discussionmentioning

confidence: 90%

“…The changes in mitochondrial morphology, reduced mito-nuclear distances, and metabolic consequences induced by DHA exposure presented here may be tied to gene expression responses involved in persister formation as a survival mechanism. These changes appear to occur in PfK13 wild-type as well as C580Y mutants and may relate to an innate, multigenic growth bistability phenomenon whereby a fraction of the drug-exposed population switches into the metabolic quiescence of persister forms, as we have discussed elsewhere (19). How is it that less than ~1% (5, 7) of the parasite population becomes persisters while the larger fraction dies away?…”

Section: Discussionmentioning

confidence: 94%

“…However, because the RSA phenotype does not include the PfK13-independent susceptibilities of more mature trophozoite-and schizont-stages, it does not correlate with standard halfmaximum inhibitory concentrations (IC50) or clinical treatments that provide continual ART exposures for more than one intraerythrocytic cycle (18). PfK13 status and the ring-stage phenotype are thus divorced from the ability of parasites to become dormant and survive ART monotherapy for periods of up to 10 days (19).…”

Section: Abstract Malaria Artemisinin-based Combination Therapy Drug Resistance Airyscan Microscopy Fluorescence Lifetime Imaging Mitochomentioning

confidence: 99%

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Restructured mitochondrial-nuclear interaction inPlasmodium falciparumdormancy and persister survival after artemisinin exposure

Connelly

Manzella-Lapeira

Levine

et al. 2020

Preprint

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Artemisinin and its semi-synthetic derivatives (ART) are fast acting, potent antimalarials; however, their use in malaria treatment is frequently confounded by recrudescences from bloodstream Plasmodium parasites that enter into and later reactivate from a dormant persister state. Here we show that the mitochondria of dihydroartemisinin (DHA)-exposed persisters are dramatically altered and enlarged relative to the mitochondria of young, actively replicating ring forms. Persister forms exhibit restructured mitochondrial-nuclear associations and an altered metabolic state consistent with stress from reactive oxygen species. New contacts between the mitochondria and nuclei may support communication pathways of mitochondrial retrograde signaling, resulting in transcriptional changes in the nucleus as a survival response. Further characterization of the organellar interactions and metabolic dependencies of persisters may suggest strategies to combat recrudescences of malaria after treatment.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 94%

Section: Abstract Malaria Artemisinin-based Combination Therapy Drug Resistance Airyscan Microscopy Fluorescence Lifetime Imaging Mitochomentioning

confidence: 99%

See 1 more Smart Citation

Restructured mitochondrial-nuclear interaction inPlasmodium falciparumdormancy and persister survival after artemisinin exposure

Connelly

Manzella-Lapeira

Levine

et al. 2020

Preprint

Self Cite

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“…In practice, day-3 parasitemia is more commonly used as a crude measure of ART resistance with 10% and 5% day-3 parasite positivity as the cut-off for suspected ART resistance in Southeast Asia and Africa, respectively ( White et al, 2015 ; WWARN Artemisinin-based Combination Therapy Africa Baseline Study Group, 2015 ). This definition of ART resistance, which deviates from classical drug resistance, has been continuously debated ( Dondorp and Ringwald, 2013 ; Ferreira et al, 2013 ; Krishna and Kremsner, 2013 ; Wellems et al, 2020 ). In fact, even before the widespread implementation of ACTs, ART monotherapies effectively cleared parasites from the blood within 7 days, but many cases recrudesced within 28 days after treatment ( Li et al, 1994 ; Looareesuwan et al, 1992b ; Nguyen et al, 1993 ), which is consistent with the RI resistance phenotype defined by the WHO ( WHO, 1965 ).…”

Section: Art Resistance: the Unusual Phenotype And Underlying Mechanismsmentioning

confidence: 99%

Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook

Siddiqui

Liang

2021

International Journal for Parasitology: Drugs and Drug Resistan

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Emergence and spread of resistance in Plasmodium falciparum to the frontline treatment artemisinin-based combination therapies (ACTs) in the epicenter of multidrug resistance of Southeast Asia threaten global malaria control and elimination. Artemisinin (ART) resistance (or tolerance) is defined clinically as delayed parasite clearance after treatment with an ART drug. The resistance phenotype is restricted to the early ring stage and can be measured in vitro using a ring-stage survival assay. ART resistance is associated with mutations in the propeller domain of the Kelch family protein K13. As a pro-drug, ART is activated primarily by heme, which is mainly derived from hemoglobin digestion in the food vacuole. Activated ARTs can react promiscuously with a wide range of cellular targets, disrupting cellular protein homeostasis. Consistent with this mode of action for ARTs, the molecular mechanisms of K13-mediated ART resistance involve reduced hemoglobin uptake/digestion and increased cellular stress response. Mutations in other genes such as AP-2μ (adaptor protein-2 μ subunit), UBP-1 (ubiquitin-binding protein-1), and Falcipain 2a that interfere with hemoglobin uptake and digestion also increase resistance to ARTs. ART resistance has facilitated the development of resistance to the partner drugs, resulting in rapidly declining ACT efficacies. The molecular markers for resistance to the partner drugs are mostly associated with point mutations in the two food vacuole membrane transporters PfCRT and PfMDR1, and amplification of pfmdr1 and the two aspartic protease genes plasmepsin 2 and 3 . It has been observed that mutations in these genes can have opposing effects on sensitivities to different partner drugs, which serve as the principle for designing triple ACTs and drug rotation. Although clinical ACT resistance is restricted to Southeast Asia, surveillance for drug resistance using in vivo clinical efficacy, in vitro assays, and molecular approaches is required to prevent or slow down the spread of resistant parasites.

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“…Delayed parasite clearance is associated with point mutations in the propeller domain of the P. falciparum Kelch 13 protein 41 and decreased parasite susceptibility to short exposures of artemisinin in vitro [42][43] . Although the delayed parasite clearance phenotype does not represent complete resistance 44 , the emergence of these parasites poses a major threat to global malaria control efforts.…”

Section: Introductionmentioning

confidence: 99%

Peroxide antimalarial drugs target redox homeostasis in Plasmodium falciparum infected red blood cells

Siddiqui

Giannangelo

Paoli

et al. 2021

Preprint

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Plasmodium falciparum causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin the frontline treatments for malaria, but artemisinin resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative. Here, we used chemoproteomics to investigate the protein alkylation targets of artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, artefenomel. We greatly expanded the list of protein targets for peroxide antimalarials and identified significant enrichment of redox-related proteins for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed by dynamic live imaging of the glutathione redox potential using a genetically encoded redox-sensitive fluorescence-based biosensor. Targeted LC-MS-based thiol metabolomics also confirmed changes in cellular thiol levels. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials.

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‘Artemisinin Resistance’: Something New or Old? Something of a Misnomer?

Cited by 29 publications

References 80 publications

Restructured mitochondrial-nuclear interaction inPlasmodium falciparumdormancy and persister survival after artemisinin exposure

Restructured mitochondrial-nuclear interaction inPlasmodium falciparumdormancy and persister survival after artemisinin exposure

Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook

Peroxide antimalarial drugs target redox homeostasis in Plasmodium falciparum infected red blood cells

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