Research ArticleMalaria

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

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Science Translational Medicine  04 Dec 2019:
Vol. 11, Issue 521, eaav1636
DOI: 10.1126/scitranslmed.aav1636

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Understanding drug resistance

Drug resistance threatens control of malaria and elimination efforts worldwide, necessitating the discovery and development of new antimalarial therapies. Mandt et al. now show that in vitro resistance to a next-generation antimalarial drug, DSM265, could be readily selected in vitro and then mimicked in vivo in a mouse infection model. An understanding of how malaria parasites develop resistance to new classes of drugs both in vitro and in vivo is an important consideration when evaluating the drug development pipeline.

Abstract

Resistance has developed in Plasmodium 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 Plasmodium falciparum to new antimalarial therapeutics. We investigated development of resistance by P. falciparum to the dihydroorotate dehydrogenase (DHODH) inhibitors DSM265 and DSM267 in tissue culture and in a mouse model of P. falciparum 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 P. falciparum 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 P. falciparum can predict development of resistance in a mouse model of malaria infection.

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