TY - JOUR
T1 - Systematic in vitro evolution in Plasmodium falciparum reveals key determinants of drug resistance
AU - Luth, Madeline R.
AU - Godinez-Macias, Karla P.
AU - Chen, Daisy
AU - Okombo, John
AU - Thathy, Vandana
AU - Cheng, Xiu
AU - Daggupati, Sindhu
AU - Davies, Heledd
AU - Dhingra, Satish K.
AU - Economy, Jan M.
AU - Edgar, Rebecca C.S.
AU - Gomez-Lorenzo, Maria G.
AU - Istvan, Eva S.
AU - Jado, Juan Carlos
AU - LaMonte, Gregory M.
AU - Melillo, Bruno
AU - Mok, Sachel
AU - Narwal, Sunil K.
AU - Ndiaye, Tolla
AU - Ottilie, Sabine
AU - Palomo Diaz, Sara
AU - Park, Heekuk
AU - Peña, Stella
AU - Rocamora, Frances
AU - Sakata-Kato, Tomoyo
AU - Small-Saunders, Jennifer L.
AU - Summers, Robert L.
AU - Tumwebaze, Patrick K.
AU - Vanaerschot, Manu
AU - Xia, Guoqin
AU - Yeo, Tomas
AU - You, Ashley
AU - Gamo, Francisco Javier
AU - Goldberg, Daniel E.
AU - Lee, Marcus C.S.
AU - McNamara, Case W.
AU - Ndiaye, Daouda
AU - Rosenthal, Philip J.
AU - Schreiber, Stuart L.
AU - Serra, Gloria
AU - De Siqueira-Neto, Jair Lage
AU - Skinner-Adams, Tina S.
AU - Uhlemann, Anne Catrin
AU - Kato, Nobutaka
AU - Lukens, Amanda K.
AU - Wirth, Dyann F.
AU - Fidock, David A.
AU - Winzeler, Elizabeth A.
PY - 2024/11/29
Y1 - 2024/11/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85211226509&partnerID=8YFLogxK
U2 - 10.1126/science.adk9893
DO - 10.1126/science.adk9893
M3 - Article
C2 - 39607932
AN - SCOPUS:85211226509
SN - 0036-8075
VL - 386
SP - eadk9893
JO - Science (New York, N.Y.)
JF - Science (New York, N.Y.)
IS - 6725
ER -