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  • Kümpornsin, KrittikornWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom; Calibr, Division of the Scripps Research Institute, CA, La Jolla, United States (author)

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

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • Springer Nature,2023
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:umu-209195
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-209195URI
  • https://doi.org/10.1038/s41467-023-38774-1DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Kochakarn, TheeraratUmeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)(Swepub:umu)thko0014 (author)
  • Yeo, TomasDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States (author)
  • Okombo, JohnDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States (author)
  • Luth, Madeline R.Department of Pediatrics, School of Medicine, University of California, San Diego, CA, La Jolla, United States (author)
  • Hoshizaki, JohannaWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom (author)
  • Rawat, MukulWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom (author)
  • Pearson, Richard D.Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom (author)
  • Schindler, Kyra A.Department of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States (author)
  • Mok, SachelDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, New York, United States (author)
  • Park, HeekukDivision of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, New York, United States (author)
  • Uhlemann, Anne-CatrinCenter for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, New York, United States; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, New York, United States (author)
  • Jana, Gouranga P.TCG Lifesciences Private Limited, Salt-lake Electronics Complex, Kolkata, India (author)
  • Maity, Bikash C.TCG Lifesciences Private Limited, Salt-lake Electronics Complex, Kolkata, India (author)
  • Laleu, BenoîtMedicines for Malaria Venture, International Centre Cointrin, Geneva, Switzerland (author)
  • Chenu, ElodieMedicines for Malaria Venture, International Centre Cointrin, Geneva, Switzerland (author)
  • Duffy, JamesMedicines for Malaria Venture, International Centre Cointrin, Geneva, Switzerland (author)
  • Moliner Cubel, SoniaGlobal Health Medicines R&D, GlaxoSmithKline, Tres Cantos, Madrid, Spain (author)
  • Franco, VirginiaGlobal Health Medicines R&D, GlaxoSmithKline, Tres Cantos, Madrid, Spain (author)
  • Gomez-Lorenzo, Maria G.Global Health Medicines R&D, GlaxoSmithKline, Tres Cantos, Madrid, Spain (author)
  • Gamo, Francisco JavierGlobal Health Medicines R&D, GlaxoSmithKline, Tres Cantos, Madrid, Spain (author)
  • Winzeler, Elizabeth A.Department of Pediatrics, School of Medicine, University of California, San Diego, CA, La Jolla, United States (author)
  • Fidock, David A.Department of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, New York, United States (author)
  • Chookajorn, ThanatUmeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet),Genomics and Evolutionary Medicine Unit, Centre of Excellence in Malaria Research, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand(Swepub:umu)thch0026 (author)
  • Lee, Marcus C. S.Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom; Biological Chemistry and Drug Discovery, Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee, United Kingdom (author)
  • Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom; Calibr, Division of the Scripps Research Institute, CA, La Jolla, United StatesMolekylär Infektionsmedicin, Sverige (MIMS) (creator_code:org_t)

Related titles

  • In:Nature Communications: Springer Nature14:12041-1723

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