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We mapped\n                    <jats:italic>k13<\/jats:italic>\n                    as the central mediator of ART resistance in vitro and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping using 34 recombinant haplotypes, and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2\/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1\/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2\/3 in mediating multigenic resistance to antimalarial agents.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adi2364","type":"journal-article","created":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T13:58:31Z","timestamp":1699451911000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":33,"title":["Mapping the genomic landscape of multidrug resistance in\n                    <i>Plasmodium falciparum<\/i>\n                    and its impact on parasite fitness"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9605-0154","authenticated-orcid":true,"given":"Sachel","family":"Mok","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Columbia University Irving Medical Center, New\u00a0York, NY, USA."},{"name":"Center for Malaria Therapeutics and Antimicrobial 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