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Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum.
Kümpornsin, Krittikorn; Kochakarn, Theerarat; Yeo, Tomas; Okombo, John; Luth, Madeline R; Hoshizaki, Johanna; Rawat, Mukul; Pearson, Richard D; Schindler, Kyra A; Mok, Sachel; Park, Heekuk; Uhlemann, Anne-Catrin; Jana, Gouranga P; Maity, Bikash C; Laleu, Benoît; Chenu, Elodie; Duffy, James; Moliner Cubel, Sonia; Franco, Virginia; Gomez-Lorenzo, Maria G; Gamo, Francisco Javier; Winzeler, Elizabeth A; Fidock, David A; Chookajorn, Thanat; Lee, Marcus C S.
Afiliación
  • Kümpornsin K; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Kochakarn T; Calibr, Division of the Scripps Research Institute, La Jolla, CA, USA.
  • Yeo T; The Laboratory for Molecular Infection Medicine Sweden and Department of Molecular Biology, Umeå University, Umeå, Sweden.
  • Okombo J; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Luth MR; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Hoshizaki J; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Rawat M; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Pearson RD; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Schindler KA; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Mok S; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Park H; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Uhlemann AC; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Jana GP; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Maity BC; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Laleu B; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Chenu E; TCG Lifesciences Private Limited, Salt-lake Electronics Complex, Kolkata, India.
  • Duffy J; TCG Lifesciences Private Limited, Salt-lake Electronics Complex, Kolkata, India.
  • Moliner Cubel S; Medicines for Malaria Venture, International Centre Cointrin, Geneva, Switzerland.
  • Franco V; Medicines for Malaria Venture, International Centre Cointrin, Geneva, Switzerland.
  • Gomez-Lorenzo MG; Medicines for Malaria Venture, International Centre Cointrin, Geneva, Switzerland.
  • Gamo FJ; Global Health Medicines R&D, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Winzeler EA; Global Health Medicines R&D, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Fidock DA; Global Health Medicines R&D, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Chookajorn T; Global Health Medicines R&D, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Lee MCS; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Nat Commun ; 14(1): 3059, 2023 05 27.
Article en En | MEDLINE | ID: mdl-37244916
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Parásitos / Malaria Falciparum / Antimaláricos Límite: Animals Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Parásitos / Malaria Falciparum / Antimaláricos Límite: Animals Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article Pais de publicación: Reino Unido