In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model

04 Dec 2019

Mandt REK, Lafuente-Monasterio MJ, Sakata-Kato T, Luth MR, Segura D, Pablos-Tanarro A, Viera S, Magan N, Ottilie S, Winzeler EA, Lukens AK, Gamo FJ, Wirth DF

Science Translational Medicine
PMID: 31801884

Doi:10.1126/scitranslmed.aav1636

Photo: Dtimiraos_iStock

Resistance has developed in malaria parasites to every antimalarial drug in clinical use, prompting the need to characterize the pathways mediating resistance. Here, we report a framework for assessing development of resistance of to new antimalarial therapeutics. We investigated development of resistance by to the dihydroorotate dehydrogenase (DHODH) inhibitors DSM265 and DSM267 in tissue culture and in a mouse model of infection. We found that resistance to these drugs arose rapidly both in vitro and in vivo. We identified 13 point mutations mediating resistance in the parasite DHODH in vitro that overlapped with the DHODH mutations that arose in the mouse infection model. Mutations in DHODH conferred increased resistance (ranging from 2- to ~400-fold) to DHODH inhibitors in in vitro and in vivo. We further demonstrated that the drug-resistant parasites carrying the C276Y mutation had mitochondrial energetics comparable to the wild-type parasite and also retained their fitness in competitive growth experiments. Our data suggest that in vitro selection of drug-resistant can predict development of resistance in a mouse model of malaria infection.

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