ArticlePLoS pathogens2022
Piperaquine-resistant PfCRT mutations differentially impact drug transport, hemoglobin catabolism and parasite physiology in Plasmodium falciparum asexual blood stages.
Article in PLoS pathogens, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 27 citations in OpenAlex.
- Identification of genetic markers of quinine partial resistance in Plasmodium falciparum.Nature microbiology · 2026Article
- Aminopeptidase Inhibition in Drug-Resistant Plasmodium falciparum: Structural, Functional, and Pharmacological Rationale for Targeting PfA-M1 and PfA-M17.ChemMedChem · 2026Review
- A Multidimensional Analysis of the Bimodal Piperaquine Response inbioRxiv : the preprint server for biology · 2026Article
- Gain-of-function PfAAT1 mutations compensate for impaired PfCRT function inResearch square · 2026Article
- Double Mutations inbioRxiv : the preprint server for biology · 2026Article
- Changing genetic profiles ofAntimicrobial agents and chemotherapy · 2026Article
- Collateral hypersensitivity between ZY19489 and piperaquine neutralizes PfCRT-mediated drug efflux and Plasmodium falciparum resistance.Nature communications · 2026Article
- Natural triterpenic phenolic esters target PfA-M17 in Plasmodium falciparum.Malaria journal · 2026Article
- Heme processing in the malaria parasite, Plasmodium falciparum: a time-dependent basal-level analysis.Communications biology · 2025Article
- Effects of recombination on multi-drug resistance evolution in Plasmodium falciparum malaria.PLoS computational biology · 2025Article
- Plasmodiumfalciparum protein kinase 6 and hemozoin formation are inhibited by a type II human kinase inhibitor exhibiting antimalarial activity.Cell chemical biology · 2025Article
- The plasmepsin-piperaquine paradox persists in Plasmodium falciparum.PLoS pathogens · 2025Article
- Plasmodium falciparum African PfCRT Mutant Isoforms Conducive to Piperaquine Resistance Are Infrequent and Impart a Major Fitness Cost.The Journal of infectious diseases · 2025Article
- Molecular basis of the functional conflict between chloroquine and peptide transport in the Malaria parasite chloroquine resistance transporter PfCRT.Nature communications · 2025Article
- Exploring bioactive molecules released during inter- and intraspecific competition: A paradigm for novel antiparasitic drug discovery and design for human use.Current research in parasitology & vector-borne diseases · 2025Review
- Dihydroartemisinin-Piperaquine Combination in the Treatment of UncomplicatedJournal of clinical medicine · 2024Review
- AmBio · 2024Article
- Article
- Assessing emergence risk of double-resistant and triple-resistant genotypes of Plasmodium falciparum.Nature communications · 2024Article
- Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
The emergence of Plasmodium falciparum parasite resistance to dihydroartemisinin + piperaquine (PPQ) in Southeast Asia threatens plans to increase the global use of this first-line antimalarial combination. High-level PPQ resistance appears to be mediated primarily by novel mutations in the P. falciparum chloroquine resistance transporter (PfCRT), which enhance parasite survival at high PPQ concentrations in vitro and increase the risk of dihydroartemisinin + PPQ treatment failure in patients. Using isogenic Dd2 parasites expressing contemporary pfcrt alleles with differential in vitro PPQ susceptibilities, we herein characterize the molecular and physiological adaptations that define PPQ resistance in vitro. Using drug uptake and cellular heme fractionation assays we report that the F145I, M343L, and G353V PfCRT mutations differentially impact PPQ and chloroquine efflux. These mutations also modulate proteolytic degradation of host hemoglobin and the chemical inactivation of reactive heme species. Peptidomic analyses reveal significantly higher accumulation of putative hemoglobin-derived peptides in the PPQ-resistant mutant PfCRT isoforms compared to parental PPQ-sensitive Dd2. Joint transcriptomic and metabolomic profiling of late trophozoites from PPQ-resistant or -sensitive isogenic lines reveals differential expression of genes involved in protein translation and cellular metabolism. PPQ-resistant parasites also show increased susceptibility to an inhibitor of the P. falciparum M17 aminopeptidase that operates on short globin-derived peptides. These results reveal unique physiological changes caused by the gain of PPQ resistance and highlight the potential therapeutic value of targeting peptide metabolism in P. falciparum.
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Registered trials
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.