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  3. In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model

In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model

  • Sci Transl Med. 2019 Dec 4;11(521):eaav1636. doi: 10.1126/scitranslmed.aav1636.
Rebecca E K Mandt 1,  Maria Jose Lafuente-Monasterio 2,  Tomoyo Sakata-Kato 1,  Madeline R Luth 3,  Delfina Segura 2,  Alba Pablos-Tanarro 2,  Sara Viera 2,  Noemi Magan 2,  Sabine Ottilie 3,  Elizabeth A Winzeler 3 4,  Amanda K Lukens 1 5,  Francisco Javier Gamo 2,  Dyann F Wirth 6 5
Affiliations

Affiliations

  • 1 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • 2 Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, 28760, Madrid, Spain.
  • 3 Division of Host Pathogen Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  • 4 Skaggs School of Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
  • 5 Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA 02142, USA.
  • 6 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. dfwirth@hsph.harvard.edu.
PMID: 31801884 DOI: 10.1126/scitranslmed.aav1636
Abstract

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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