{"doi":"10.1093/infdis/jiac365","title":"Mutant PfCRT Can Mediate Piperaquine Resistance in African <i>Plasmodium falciparum</i> With Reduced Fitness and Increased Susceptibility to Other Antimalarials","abstract":"BACKGROUND: Additional therapeutic strategies could benefit efforts to reverse the recent increase in malaria cases in sub-Saharan Africa, which mostly affects young children. A primary candidate is dihydroartemisinin + piperaquine (DHA + PPQ), which is effective for uncomplicated malaria treatment, seasonal malaria chemoprevention, and intermittent preventive treatment. In Southeast Asia, Plasmodium falciparum parasites acquired PPQ resistance, mediated primarily by mutations in the P falciparum chloroquine resistance transporter PfCRT. The recent emergence in Africa of DHA-resistant parasites creates an imperative to assess whether PPQ resistance could emerge in African parasites with distinct PfCRT isoforms. METHODS: We edited 2 PfCRT mutations known to mediate high-grade PPQ resistance in Southeast Asia into GB4 parasites from Gabon. Gene-edited clones were profiled in antimalarial concentration-response and fitness assays. RESULTS: The PfCRT F145I mutation mediated moderate PPQ resistance in GB4 parasites but with a substantial fitness cost. No resistance was observed with the PfCRT G353V mutant. Both edited clones became significantly more susceptible to amodiaquine, chloroquine, and quinine. CONCLUSIONS: A single PfCRT mutation can mediate PPQ resistance in GB4 parasites, but with a growth defect that may preclude its spread without further genetic adaptations. Our findings support regional use of drug combinations that exert opposing selective pressures on PfCRT.","journal":"The Journal of Infectious Diseases","year":2022,"id":247280,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":626326,"name":"Jennifer L. Small-Saunders","orcid":"0000-0001-6064-2249","position":1,"is_corresponding":false},{"id":884747,"name":"Laura M. Hagenah","orcid":"0000-0001-8258-6823","position":2,"is_corresponding":false},{"id":249734,"name":"Sachel Mok","orcid":"0000-0002-9605-0154","position":3,"is_corresponding":false},{"id":107758,"name":"David A. Fidock","orcid":"0000-0001-6753-8938","position":4,"is_corresponding":false},{"id":288351,"name":"Kathryn J. Wicht","orcid":"0000-0001-6145-9956","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T00:23:53.369530Z","pmid":"36082431","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}