biostudies-literatureOkombo JNational Institute of Allergy and Infectious DiseasesHuman Frontier Science ProgramNIAID NIH HHSNIEHS NIH HHSe1010926https://www.ebi.ac.uk/biostudies/studies/S-EPMC9645663biostudies-literatureUnknown18(10)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 F145IPLoS pathogensPiperaquine-resistant PfCRT mutations differentially impact drug transport, hemoglobin catabolism and parasite physiology in Plasmodium falciparum asexual blood stages.PMC9645663R01 AI05234R01 AI147628R37 AI050234R01 AI124678LT000976/2016-LT32 ES007020R21 AI159558Bath JKoo IQahash TYeo TAlbert ILlinas MOwens EFidock DAOrchard LMMok SOkombo JfalsePiperaquine-resistant PfCRT mutations differentially impact drug transport, hemoglobin catabolism and parasite physiology in Plasmodium falciparum asexual blood stages.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 F145I2022-01-01T00:00:00Z2022 Oct2026-05-28T21:28:36.359Z2025-04-19T22:49:12.051ZS-EPMC96456633630628710.1371/journal.ppat.1010926