Systematic in vitro evolution in reveals key determinants of drug resistance.
Journal:
Science (New York, N.Y.), Volume: 386, Issue: 6725
Published:
November 29, 2024
Authors:
Madeline R Luth MR, Karla P Godinez-Macias KP, Daisy Chen D, John Okombo J, Vandana Thathy V, Xiu Cheng X, Sindhu Daggupati S, Heledd Davies H, Satish K Dhingra SK, Jan M Economy JM, Rebecca C S Edgar RCS, Maria G Gomez-Lorenzo MG, Eva S Istvan ES, Juan Carlos Jado JC, Gregory M LaMonte GM, Bruno Melillo B, Sachel Mok S, Sunil K Narwal SK, Tolla Ndiaye T, Sabine Ottilie S, Sara Palomo Diaz S, Heekuk Park H, Stella Peña S, Frances Rocamora F, Tomoyo Sakata-Kato T, Jennifer L Small-Saunders JL, Robert L Summers RL, Patrick K Tumwebaze PK, Manu Vanaerschot M, Guoqin Xia G, Tomas Yeo T, Ashley You A, Francisco-Javier Gamo FJ, Daniel E Goldberg DE, Marcus C S Lee MCS, Case W McNamara CW, Daouda Ndiaye D, Philip J Rosenthal PJ, Stuart L Schreiber SL, Gloria Serra G, Jair Lage De Siqueira-Neto JL, Tina S Skinner-Adams TS, Anne-Catrin Uhlemann AC, Nobutaka Kato N, Amanda K Lukens AK, Dyann F Wirth DF, David A Fidock DA, Elizabeth A Winzeler EA
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 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 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.
Courtesy of the U.S. National Library of Medicine
