biostudies-literatureLuth MRNIAID NIH HHSGates FoundationNIH HHSNIGMS NIH HHSeadk9893https://www.ebi.ac.uk/biostudies/studies/S-EPMC11809290biostudies-literatureUnknown386(6725)Surveillance of drug resistance and the discovery of novel targets-key objectives in the fight against malaria-rely on identifying resistance-conferring mutations in <i>Plasmodium</i> parasites. Current approaches, while successful, require laborious experimentation or large sample sizes. To elucidate shared determinants of antimalarial resistance that can empower in silico inference, we examined the genomes of 724 <i>Plasmodium falciparum</i> clones, each selected in vitro for resistance to one of 118 compounds. We identified 1448 variants in 128 recurrently mutated genes, including drivers of antimalarial multidrug resistance. In contrast to naturally occurring variants, those selected in vitro are more likely to be missense or frameshift, involve bulky substitutions, and occur in conserScience (New York, N.Y.)Systematic in vitro evolution in &lt;i&gt;Plasmodium falciparum&lt;/i&gt; reveals key determinants of drug resistance.PMC11809290R01 AI185559R01 AI152533R01 AI154777R01 AI182318R01 AI103058T32 GM008666R01 AI172066T32 GM139790R37 AI050234INV-008249S10 OD026929R01 AI124678R01 AI109023R01 AI169892De Siqueira-Neto JLSummers RLOttilie SFidock DAThathy VUhlemann ACSakata-Kato TCheng XLaMonte GMLukens AKMcNamara CWIstvan ESKato NGodinez-Macias KPNdiaye DWinzeler EAPalomo Diaz SLuth MRGamo FJLee MCSOkombo JNarwal SKXia GWirth DFMelillo BPark HYeo TGoldberg DEVanaerschot MDhingra SKRocamora FGomez-Lorenzo MGNdiaye TDaggupati SSerra GSkinner-Adams TSMok SChen DJado JCSchreiber SLEconomy JMDavies HSmall-Saunders JLYou APena SEdgar RCSTumwebaze PKRosenthal PJfalseSystematic in vitro evolution in &lt;i&gt;Plasmodium falciparum&lt;/i&gt; reveals key determinants of drug resistance.Surveillance of drug resistance and the discovery of novel targets-key objectives in the fight against malaria-rely on identifying resistance-conferring mutations in <i>Plasmodium</i> parasites. Current approaches, while successful, require laborious experimentation or large sample sizes. To elucidate shared determinants of antimalarial resistance that can empower in silico inference, we examined the genomes of 724 <i>Plasmodium falciparum</i> clones, each selected in vitro for resistance to one of 118 compounds. We identified 1448 variants in 128 recurrently mutated genes, including drivers of antimalarial multidrug resistance. In contrast to naturally occurring variants, those selected in vitro are more likely to be missense or frameshift, involve bulky substitutions, and occur in conser2024-01-01T00:00:00Z2024 Nov2026-06-01T13:13:17.313Z2025-04-04T13:11:47.866ZS-EPMC118092903960793210.1126/science.adk9893