Systematic in vitro evolution in Plasmodium falciparum reveals key determinants of drug resistance

• 成果类型: Article
• 署名作者: Luth, Madeline R.; Godinez-Macias, Karla P.; Chen, Daisy; Okombo, John; Thathy, Vandana; Cheng, Xiu; Daggupati, Sindhu; Davies, Heledd; Dhingra, Satish K.; Economy, Jan M.; Edgar, Rebecca C. S.; Gomez-Lorenzo, Maria G.; Istvan, Eva S.; Jado, Juan Carlos; Lamonte, Gregory M.; Melillo, Bruno; Mok, Sachel; Narwal, Sunil K.; Ndiaye, Tolla; Ottilie, Sabine; Palomo Diaz, Sara; Park, Heekuk; Pena, Stella; Rocamora, Frances; Sakata-Kato, Tomoyo; Small-Saunders, Jennifer L.; Summers, Robert L.; Tumwebaze, Patrick K.; Vanaerschot, Manu; Xia, Guoqin; Yeo, Tomas; You, Ashley; Gamo, Francisco-Javier; Goldberg, Daniel E.; Lee, Marcus C. S.; Mcnamara, Case W.; Ndiaye, Daouda; Rosenthal, Philip J.; Schreiber, Stuart L.; Serra, Gloria; De Siqueira-Neto, Jair Lage; Skinner-Adams, Tina S.; Uhlemann, Anne-Catrin; Kato, Nobutaka; Lukens, Amanda K.; Wirth, Dyann F.; Fidock, David A.; Winzeler, Elizabeth A.
• 署名单位: University of California System; University of California San Diego; NewYork-Presbyterian Hospital; Columbia University; NewYork-Presbyterian Hospital; Columbia University; Wellcome Trust Sanger Institute; University of Dundee; GlaxoSmithKline; Glaxosmithkline Spain; Washington University (WUSTL); Washington University (WUSTL); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; NewYork-Presbyterian Hospital; Columbia University; Universidad de la Republica, Uruguay; Nagasaki University; Harvard University; Harvard T.H. Chan School of Public Health; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Scripps Research Institute; Scripps Research Institute; University of California System; University of California San Francisco; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of California System; University of California San Diego; Griffith University; Griffith University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9556
• DOI: 10.1126/science.adk9893
• 发表日期: 2024-11-29
• 关键词: chloroquine resistance; malaria parasites; small-molecule; blood-stage; inhibition; mutations; protein; transporter; genome; loci

摘要

Surveillance of drug resistance and the discovery of novel targets-key objectives in the fight against malaria-rely on identifying resistance-conferring mutations in Plasmodium 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 Plasmodium falciparum 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 conserved, ordered protein domains. Collectively, our dataset reveals mutation features that predict drug resistance in eukaryotic pathogens.