Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum
Issued Date
2023-12-01
Resource Type
eISSN
20411723
Scopus ID
2-s2.0-85160271952
Journal Title
Nature Communications
Volume
14
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nature Communications Vol.14 No.1 (2023)
Suggested Citation
Kümpornsin K., Kochakarn T., Yeo T., Okombo J., Luth M.R., Hoshizaki J., Rawat M., Pearson R.D., Schindler K.A., Mok S., Park H., Uhlemann A.C., Jana G.P., Maity B.C., Laleu B., Chenu E., Duffy J., Moliner Cubel S., Franco V., Gomez-Lorenzo M.G., Gamo F.J., Winzeler E.A., Fidock D.A., Chookajorn T., Lee M.C.S. Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum. Nature Communications Vol.14 No.1 (2023). doi:10.1038/s41467-023-38774-1 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/82930
Title
Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum
Author's Affiliation
Other Contributor(s)
Abstract
In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however, key obstacles to eliciting resistance are the parasite inoculum size and mutation rate. Here we sought to increase parasite genetic diversity to potentiate resistance selections by editing catalytic residues of Plasmodium falciparum DNA polymerase δ. Mutation accumulation assays reveal a ~5–8 fold elevation in the mutation rate, with an increase of 13–28 fold in drug-pressured lines. Upon challenge with the spiroindolone PfATP4-inhibitor KAE609, high-level resistance is obtained more rapidly and at lower inocula than wild-type parasites. Selections also yield mutants with resistance to an “irresistible” compound, MMV665794 that failed to yield resistance with other strains. We validate mutations in a previously uncharacterised gene, PF3D7_1359900, which we term quinoxaline resistance protein (QRP1), as causal for resistance to MMV665794 and a panel of quinoxaline analogues. The increased genetic repertoire available to this “mutator” parasite can be leveraged to drive P. falciparum resistome discovery.