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Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom; Calibr, Division of the Scripps Research Institute, CA, La Jolla, United States.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
Department of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States.
Department of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States.
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 3059Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer Nature, 2023. Vol. 14, no 1, article id 3059
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Cell and Molecular Biology Infectious Medicine Genetics
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URN: urn:nbn:se:umu:diva-209195DOI: 10.1038/s41467-023-38774-1ISI: 000996589500005PubMedID: 37244916Scopus ID: 2-s2.0-85160271952OAI: oai:DiVA.org:umu-209195DiVA, id: diva2:1763965
Available from: 2023-06-08 Created: 2023-06-08 Last updated: 2023-09-05Bibliographically approved

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Kochakarn, TheeraratChookajorn, Thanat

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Kochakarn, TheeraratChookajorn, Thanat
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Molecular Infection Medicine Sweden (MIMS)Department of Molecular Biology (Faculty of Science and Technology)
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Nature Communications
Cell and Molecular BiologyInfectious MedicineGenetics

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