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In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model.
Mandt, Rebecca E K; Lafuente-Monasterio, Maria Jose; Sakata-Kato, Tomoyo; Luth, Madeline R; Segura, Delfina; Pablos-Tanarro, Alba; Viera, Sara; Magan, Noemi; Ottilie, Sabine; Winzeler, Elizabeth A; Lukens, Amanda K; Gamo, Francisco Javier; Wirth, Dyann F.
Afiliación
  • Mandt REK; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • Lafuente-Monasterio MJ; Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, 28760, Madrid, Spain.
  • Sakata-Kato T; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • Luth MR; Division of Host Pathogen Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • Segura D; Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, 28760, Madrid, Spain.
  • Pablos-Tanarro A; Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, 28760, Madrid, Spain.
  • Viera S; Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, 28760, Madrid, Spain.
  • Magan N; Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, 28760, Madrid, Spain.
  • Ottilie S; Division of Host Pathogen Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • Winzeler EA; Division of Host Pathogen Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • Lukens AK; Skaggs School of Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
  • Gamo FJ; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • Wirth DF; Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142, USA.
Sci Transl Med ; 11(521)2019 12 04.
Article en En | MEDLINE | ID: mdl-31801884
Resistance has developed in Plasmodium malaria parasites to every antimalarial drug in clinical use, prompting the need to characterize the pathways mediating resistance. Here, we report a framework for assessing development of resistance of Plasmodium falciparum to new antimalarial therapeutics. We investigated development of resistance by P. falciparum to the dihydroorotate dehydrogenase (DHODH) inhibitors DSM265 and DSM267 in tissue culture and in a mouse model of P. falciparum infection. We found that resistance to these drugs arose rapidly both in vitro and in vivo. We identified 13 point mutations mediating resistance in the parasite DHODH in vitro that overlapped with the DHODH mutations that arose in the mouse infection model. Mutations in DHODH conferred increased resistance (ranging from 2- to ~400-fold) to DHODH inhibitors in P. falciparum in vitro and in vivo. We further demonstrated that the drug-resistant parasites carrying the C276Y mutation had mitochondrial energetics comparable to the wild-type parasite and also retained their fitness in competitive growth experiments. Our data suggest that in vitro selection of drug-resistant P. falciparum can predict development of resistance in a mouse model of malaria infection.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Parásitos / Malaria Falciparum / Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH / Inhibidores Enzimáticos Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Parásitos / Malaria Falciparum / Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH / Inhibidores Enzimáticos Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos