ArticleMalaria journal2020
Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization.
Article in Malaria journal, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 3 of them syntheses that pooled it.
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Who cites it
28 citing papers in PubMed, 3 syntheses or guidelines pooled it, 43 citations in OpenAlex.
- Prevalence of Plasmodium falciparum plasmepsin2/3 gene duplication in Africa and Asia: a systematic review and meta-analysis.Malaria journal · 2025Pooled it
- How has mass drug administration with dihydroartemisinin-piperaquine impacted molecular markers of drug resistance? A systematic review.Malaria journal · 2022Pooled 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
- A Multidimensional Analysis of the Bimodal Piperaquine Response inbioRxiv : the preprint server for biology · 2026Article
- Impact of intensive control on malaria population genomics under elimination settings in Southeast Asia.Nature microbiology · 2026Article
- Frequencies of molecular markers of drug resistance in the context of two different Seasonal Malaria Chemoprevention (SMC) treatment regimens in the Koulikoro health district, Mali.Antimicrobial agents and chemotherapy · 2025Article
- No evidence of molecular markers of piperaquine resistance in southeastern Nigeria.Malaria journal · 2025Article
- Innovations in Antimalarial Drug Discovery: New Targets and Leads.Current drug targets · 2025Review
- Dihydroartemisinin-Piperaquine Combination in the Treatment of UncomplicatedJournal of clinical medicine · 2024Review
- Screening of the Pandemic Response Box library identified promising compound candidate drug combinations against extensively drug-resistant Acinetobacter baumannii.Scientific reports · 2024Article
- AmBio · 2024Article
- Novel quinolinepiperazinyl-aryltetrazoles targeting the blood stage ofRSC medicinal chemistry · 2024Article
- The landscape of drug resistance in Plasmodium falciparum malaria in the Democratic Republic of Congo: a mapping systematic review.Tropical medicine and health · 2023Review
- Evolution of genetic markers for drug resistance after the introduction of dihydroartemisinin-piperaquine as first-line anti-malarial treatment for uncomplicated falciparum malaria in Indonesia.Malaria journal · 2023Article
- PfCRT mutations conferring piperaquine resistance in falciparum malaria shape the kinetics of quinoline drug binding and transport.PLoS pathogens · 2023Article
- Malaria Control by Mass Drug Administration With Artemisinin Plus Piperaquine on Grande Comore Island, Union of Comoros.Open forum infectious diseases · 2023Article
- Drug Development Strategies for Malaria: With the Hope for New Antimalarial Drug Discovery-An Update.Advances in medicine · 2023Review
- Article
- Molecular surveillance of artemisinin resistance-related Pfk13 and pfcrt polymorphisms in imported Plasmodium falciparum isolates reported in eastern China from 2015 to 2019.Malaria journal · 2022Article
- Molecular markers of dihydroartemisinin-piperaquine resistance in northwestern Thailand.Malaria journal · 2022Article
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19 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHigh rates of dihydroartemisinin-piperaquine (DHA-PPQ) treatment failures have been documented for uncomplicated Plasmodium falciparum in Cambodia. The genetic markers plasmepsin 2 (pfpm2), exonuclease (pfexo) and chloroquine resistance transporter (pfcrt) genes are associated with PPQ resistance and are used for monitoring the prevalence of drug resistance and guiding malaria drug treatment policy.
methodsTo examine the relative contribution of each marker to PPQ resistance, in vitro culture and the PPQ survival assay were performed on seventeen P. falciparum isolates from northern Cambodia, and the presence of E415G-Exo and pfcrt mutations (T93S, H97Y, F145I, I218F, M343L, C350R, and G353V) as well as pfpm2 copy number polymorphisms were determined. Parasites were then cloned by limiting dilution and the cloned parasites were tested for drug susceptibility. Isobolographic analysis of several drug combinations for standard clones and newly cloned P. falciparum Cambodian isolates was also determined.
resultsThe characterization of culture-adapted isolates revealed that the presence of novel pfcrt mutations (T93S, H97Y, F145I, and I218F) with E415G-Exo mutation can confer PPQ-resistance, in the absence of pfpm2 amplification. In vitro testing of PPQ resistant parasites demonstrated a bimodal dose-response, the existence of a swollen digestive vacuole phenotype, and an increased susceptibility to quinine, chloroquine, mefloquine and lumefantrine. To further characterize drug sensitivity, parental parasites were cloned in which a clonal line, 14-B5, was identified as sensitive to artemisinin and piperaquine, but resistant to chloroquine. Assessment of the clone against a panel of drug combinations revealed antagonistic activity for six different drug combinations. However, mefloquine-proguanil and atovaquone-proguanil combinations revealed synergistic antimalarial activity.
conclusionsSurveillance for PPQ resistance in regions relying on DHA-PPQ as the first-line treatment is dependent on the monitoring of molecular markers of drug resistance. P. falciparum harbouring novel pfcrt mutations with E415G-exo mutations displayed PPQ resistant phenotype. The presence of pfpm2 amplification was not required to render parasites PPQ resistant suggesting that the increase in pfpm2 copy number alone is not the sole modulator of PPQ resistance. Genetic background of circulating field isolates appear to play a role in drug susceptibility and biological responses induced by drug combinations. The use of latest field isolates may be necessary for assessment of relevant drug combinations against P. falciparum strains and when down-selecting novel drug candidates.
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