ArticleAntimicrobial agents and chemotherapy2011
Piperaquine resistance is associated with a copy number variation on chromosome 5 in drug-pressured Plasmodium falciparum parasites.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers, 1 of them a synthesis that pooled it.
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Who cites it
81 citing papers in PubMed, 1 synthesis or guideline pooled it, 107 citations in OpenAlex.
- Plasmodium falciparum antimalarial resistance in Angola: a systematic review.Malaria journal · 2026Pooled it
- Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.Lancet (London, England) · 2020Trial
- Sequential Open-Label Study of the Safety, Tolerability, and Pharmacokinetic Interactions between Dihydroartemisinin-Piperaquine and Mefloquine in Healthy Thai Adults.Antimicrobial agents and chemotherapy · 2019Trial
- Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children.Malaria journal · 2015Trial
- Randomized Noninferiority Trial of Dihydroartemisinin-Piperaquine Compared with Sulfadoxine-Pyrimethamine plus Amodiaquine for Seasonal Malaria Chemoprevention in Burkina Faso.Antimicrobial agents and chemotherapy · 2015Trial
- Antimalarial drug resistance inParasitology · 2026Article
- Tolerance of Plasmodium falciparum mefloquine-resistant clinical isolates to mefloquine-piperaquine with implications for triple artemisinin-based combination therapies.Nature communications · 2025Article
- Defining the next generation of severe malaria treatment: a target product profile.Malaria journal · 2024Review
- 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
- Plasmodium falciparum merozoite invasion ligands, linked antimalarial resistance loci and ex vivo responses to antimalarials in The Gambia.The Journal of antimicrobial chemotherapy · 2022Article
- Piperaquine-resistant PfCRT mutations differentially impact drug transport, hemoglobin catabolism and parasite physiology in Plasmodium falciparum asexual blood stages.PLoS pathogens · 2022Article
- Whole Genome Sequencing Contributions and Challenges in Disease Reduction Focused on Malaria.Biology · 2022Review
- Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook.International journal for parasitology. Drugs and drug resistance · 2021Article
- Artemisinin susceptibility in the malaria parasite Plasmodium falciparum: propellers, adaptor proteins and the need for cellular healing.FEMS microbiology reviews · 2021Review
- Molecular surveillance of anti-malarial resistance pfcrt, pfmdr1, and pfk13 polymorphisms in African Plasmodium falciparum imported parasites to Wuhan, China.Malaria journal · 2021Article
- PfMFR3: A Multidrug-Resistant Modulator inACS infectious diseases · 2021Article
- Isolation of Mutants With Reduced Susceptibility to Piperaquine From a Mutator of the Rodent Malaria ParasiteFrontiers in cellular and infection microbiology · 2021Article
- Modulation of Triple Artemisinin-Based Combination Therapy Pharmacodynamics byACS pharmacology & translational science · 2020Article
- Article
- Unsymmetrical Bisquinolines with High Potency againstMolecules (Basel, Switzerland) · 2020Article
21 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
The combination of piperaquine and dihydroartemisinin has recently become the official first-line therapy in several Southeast Asian countries. The pharmacokinetic mismatching of these drugs, whose plasma half-lives are ~20 days and ~1 h, respectively, implies that recrudescent or new infections emerging shortly after treatment cessation will encounter piperaquine as a monotherapy agent. This creates substantial selection pressure for the emergence of resistance. To elucidate potential resistance determinants, we subjected cloned Plasmodium falciparum Dd2 parasites to continuous piperaquine pressure in vitro (47 nM; ~2-fold higher than the Dd2 50% inhibitory concentration [IC(50)]). The phenotype of outgrowth parasites was assayed in two clones, revealing an IC(50) against piperaquine of 2.1 μM and 1.7 μM, over 100-fold greater than that of the parent. To identify the genetic determinant of resistance, we employed comparative whole-genome hybridization analysis. Compared to the Dd2 parent, this analysis found (in both resistant clones) a novel single-nucleotide polymorphism in P. falciparum crt (pfcrt), deamplification of an 82-kb region of chromosome 5 (that includes pfmdr1), and amplification of an adjacent 63-kb region of chromosome 5. Continued propagation without piperaquine selection pressure resulted in "revertant" piperaquine-sensitive parasites. These retained the pfcrt polymorphism and further deamplified the chromosome 5 segment that encompasses pfmdr1; however, these two independently generated revertants both lost the neighboring 63-kb amplification. These results suggest that a copy number variation event on chromosome 5 (825600 to 888300) is associated with piperaquine resistance. Transgene expression studies are underway with individual genes in this segment to evaluate their contribution to piperaquine resistance.
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