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

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 - https://www.scopus.com/pages/publications/85211226509

U2 - 10.1126/science.adk9893

DO - 10.1126/science.adk9893

M3 - Article

C2 - 39607932

AN - SCOPUS:85211226509

SN - 0036-8075

VL - 386

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6725

M1 - eadk9893

ER -