Systematic in vitro evolution in <i>Plasmodium falciparum</i> reveals key determinants of drug resistance
Madeline R. Luth, Karla P. Godinez‐Macias, Daisy Chen, John Okombo, Vandana Thathy, Xiu Cheng, Sindhu Daggupati, Heledd Davies, Satish K. Dhingra, James Economy, Rebecca Edgar, Marı́a G. Gómez-Lorenzo, Eva S. Istvan, Juan Carlos Jado, Gregory LaMonte, Bruno Melillo, Sachel Mok, Sunil Kumar Narwal, Tolla Ndiaye, Sabine Ottilie, Sara Palomo Dı́az, Heekuk Park, Stella Peña, Frances Rocamora, Tomoyo Sakata‐Kato, Jennifer L. Small-Saunders, Robert L. Summers, Patrick K. Tumwebaze, Manu Vanaerschot, Guoqin Xia, Tomas Yeo, Ashley You, Francisco‐Javier Gamo, Daniel E. Goldberg, Lee M, Case W. McNamara, Daouda Ndiaye, Philip J. Rosenthal, Stuart L. Schreiber, Gloria Serra, Jair L. Siqueira-Neto, Tina S. Skinner‐Adams, Anne‐Catrin Uhlemann, Nobutaka Kato, Amanda K. Lukens, Dyann F. Wirth, David A. Fidock, Elizabeth A. Winzeler
Abstract
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.