ArticleProceedings of the National Academy of Sciences of the United States of America2013
Altered temporal response of malaria parasites determines differential sensitivity to artemisinin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 126 papers, 2 of them syntheses that pooled it.
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Who cites it
126 citing papers in PubMed, 2 syntheses or guidelines pooled it, 217 citations in OpenAlex.
- Efficacy and safety of artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Ethiopia: a systematic review and meta-analysis.Malaria journal · 2021Pooled it
- Artemisinin-based combination therapy (ACT) and drug resistance molecular markers: A systematic review of clinical studies from two malaria endemic regions - India and sub-Saharan Africa.International journal for parasitology. Drugs and drug resistance · 2021Pooled it
- Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria.PloS one · 2017Trial
- Single-cell transcriptional changes of artemisinin-sensitive K13Frontiers in cellular and infection microbiology · 2026Article
- Article
- Single-cell transcriptional changes across the blood stages of artemisinin-resistant K13bioRxiv : the preprint server for biology · 2025Article
- Synthesis and SAR Studies of Acyl-Thiourea Platinum(II) Complexes Yield Analogs with Dual-Stage Antiplasmodium Activity.ACS medicinal chemistry letters · 2025Article
- Isolation and characterization ofAntimicrobial agents and chemotherapy · 2025Article
- Artemisinin pressure in field isolates can select highly resistantAntimicrobial agents and chemotherapy · 2025Article
- Stage-specific pharmacodynamic chloroquine and pyronaridine action on artemisinin ring-stage resistant Kelch C580Y mutationAntimicrobial agents and chemotherapy · 2025Article
- Artemisinin-resistant malaria.Clinical microbiology reviews · 2024Review
- A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo.PLoS pathogens · 2024Article
- Enhanced cell stress response and protein degradation capacity underlie artemisinin resistance inmSphere · 2024Article
- An adaptable, fit-for-purpose screening approach with high-throughput capability to determine speed of action and stage specificity of anti-malarial compounds.Antimicrobial agents and chemotherapy · 2024Article
- A fast-acting inhibitor of blood-stagebioRxiv : the preprint server for biology · 2024Article
- Article
- Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases.Journal of medicinal chemistry · 2024Article
- Trio fluorophore-based phenotypic assay for the detection of artemisinin-induced growth-arrested Plasmodium falciparum in human erythrocytes.Scientific reports · 2024Article
- The Kelch13 compartment contains highly divergent vesicle trafficking proteins in malaria parasites.PLoS pathogens · 2023Article
- An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria.The Journal of antimicrobial chemotherapy · 2023Article
66 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Reports of emerging resistance to first-line artemisinin antimalarials make it critical to define resistance mechanisms and identify in vitro correlates of resistance. Here we combine unique in vitro experimental and analytical approaches to mimic in vivo drug exposure in an effort to provide insight into mechanisms of drug resistance. Tightly synchronized parasites exposed to short drug pulses exhibit large stage-dependent differences in their drug response that correlate with hemoglobin digestion throughout most of the asexual cycle. As a result, ring-stage parasites can exhibit >100-fold lower sensitivity to short drug pulses than trophozoites, although we identify a subpopulation of rings (2-4 h postinvasion) that exhibits hypersensitivity. We find that laboratory strains that show little differences in drug sensitivity in standard in vitro assays exhibit substantial (>95-fold) difference in sensitivity when exposed to short drug pulses. These stage- and strain-dependent differences in drug sensitivity reflect differential response lag times with rings exhibiting lag times of up to 4 h. A simple model that assumes that the parasite experiences a saturable effective drug dose describes the complex dependence of parasite viability on both drug concentration and exposure time and is used to demonstrate that small changes in the parasite's drug response profile can dramatically alter the sensitivity to artemisinins. This work demonstrates that effective resistance can arise from the interplay between the short in vivo half-life of the drug and the stage-specific lag time and provides the framework for understanding the mechanisms of drug action and parasite resistance.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.