Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, United States; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States
Sudipta Das
Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, Philadelphia, United States
Suyash Bhatnagar
Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, Philadelphia, United States
Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, United States; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States
Edward Owen
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, United States; Huck Center for Malaria Research, Pennsylvania State University, University Park, United States; Department of Chemistry, Pennsylvania State University, University Park, United States
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, United States; Huck Center for Malaria Research, Pennsylvania State University, University Park, United States; Department of Chemistry, Pennsylvania State University, University Park, United States
Suresh M Ganesan
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
Jacquin C Niles
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, United States; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States
Plasmodium parasites possess a protein with homology to Niemann-Pick Type C1 proteins (Niemann-Pick Type C1-Related protein, NCR1). We isolated parasites with resistance-conferring mutations in Plasmodium falciparum NCR1 (PfNCR1) during selections with three diverse small-molecule antimalarial compounds and show that the mutations are causative for compound resistance. PfNCR1 protein knockdown results in severely attenuated growth and confers hypersensitivity to the compounds. Compound treatment or protein knockdown leads to increased sensitivity of the parasite plasma membrane (PPM) to the amphipathic glycoside saponin and engenders digestive vacuoles (DVs) that are small and malformed. Immuno-electron microscopy and split-GFP experiments localize PfNCR1 to the PPM. Our experiments show that PfNCR1 activity is critically important for the composition of the PPM and is required for DV biogenesis, suggesting PfNCR1 as a novel antimalarial drug target.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
