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

Sci Transl Med
Authors
Keywords
Abstract

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.

Year of Publication
2019
Journal
Sci Transl Med
Volume
11
Issue
521
Date Published
2019 12 04
ISSN
1946-6242
DOI
10.1126/scitranslmed.aav1636
PubMed ID
31801884
PubMed Central ID
PMC7444640
Links
Grant list
R01 AI093716 / AI / NIAID NIH HHS / United States
T32 GM008666 / GM / NIGMS NIH HHS / United States