Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum

Krittikorn Kümpornsin, Theerarat Kochakarn, Tomas Yeo, John Okombo, Madeline R. Luth, Johanna Hoshizaki, Mukul Rawat, Richard D. Pearson, Kyra A. Schindler, Sachel Mok, Heekuk Park, Anne-Catrin Uhlemann, Gouranga P. Jana, Bikash C. Maity, Benoît Laleu, Elodie Chenu, James Duffy, Sonia Moliner Cubel, Virginia Franco, Maria G. Gomez-Lorenzo, Francisco Javier Gamo, Elizabeth A. Winzeler, David A. Fidock, Thanat Chookajorn and Marcus C. S. Lee ()
Additional contact information
Krittikorn Kümpornsin: Wellcome Genome Campus
Theerarat Kochakarn: Umeå University
Tomas Yeo: Columbia University Irving Medical Center
John Okombo: Columbia University Irving Medical Center
Madeline R. Luth: University of California, San Diego
Johanna Hoshizaki: Wellcome Genome Campus
Mukul Rawat: Wellcome Genome Campus
Richard D. Pearson: Wellcome Genome Campus
Kyra A. Schindler: Columbia University Irving Medical Center
Sachel Mok: Columbia University Irving Medical Center
Heekuk Park: Columbia University Irving Medical Center
Anne-Catrin Uhlemann: Columbia University Irving Medical Center
Gouranga P. Jana: Salt-lake Electronics Complex
Bikash C. Maity: Salt-lake Electronics Complex
Benoît Laleu: International Centre Cointrin
Elodie Chenu: International Centre Cointrin
James Duffy: International Centre Cointrin
Sonia Moliner Cubel: GlaxoSmithKline, Tres Cantos
Virginia Franco: GlaxoSmithKline, Tres Cantos
Maria G. Gomez-Lorenzo: GlaxoSmithKline, Tres Cantos
Francisco Javier Gamo: GlaxoSmithKline, Tres Cantos
Elizabeth A. Winzeler: University of California, San Diego
David A. Fidock: Columbia University Irving Medical Center
Thanat Chookajorn: Umeå University
Marcus C. S. Lee: Wellcome Genome Campus

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38774-1

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