2. Academic Validation
  3. PfMFR3: A Multidrug-Resistant Modulator in Plasmodium falciparum

PfMFR3: A Multidrug-Resistant Modulator in Plasmodium falciparum

  • ACS Infect Dis. 2021 Apr 9;7(4):811-825. doi: 10.1021/acsinfecdis.0c00676.
Frances Rocamora 1,  Purva Gupta 2 3,  Eva S Istvan 4,  Madeline R Luth 1,  Emma F Carpenter 5,  Krittikorn Kümpornsin 5,  Erika Sasaki 1,  Jaeson Calla 1,  Nimisha Mittal 1,  Krypton Carolino 1,  Edward Owen 6 7,  Manuel Llinás 6 7 8,  Sabine Ottilie 1,  Daniel E Goldberg 4,  Marcus C S Lee 5,  Elizabeth A Winzeler 1
Affiliations

Affiliations

  • 1 Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, United States.
  • 2 VA San Diego Healthcare System, Medical and Research Sections, La Jolla, California 92161, United States.
  • 3 Department of Medicine, Division of Pulmonary and Critical Care, University of California, San Diego, La Jolla, California 92037, United States.
  • 4 Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63130, United States.
  • 5 Wellcome Sanger Institute, Hinxton CB10 1SA, United Kingdom.
  • 6 Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, United States.
  • 7 Huck Center for Malaria Research, Pennsylvania State University, University Park, Pennsylvania 16802, United States.
  • 8 Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, United States.
PMID: 33715347 DOI: 10.1021/acsinfecdis.0c00676
Abstract

In malaria, chemical genetics is a powerful method for assigning function to uncharacterized genes. MMV085203 and GNF-Pf-3600 are two structurally related napthoquinone phenotypic screening hits that kill both blood- and sexual-stage P. falciparum parasites in the low nanomolar to low micromolar range. In order to understand their mechanism of action, parasites from two different genetic backgrounds were exposed to sublethal concentrations of MMV085203 and GNF-Pf-3600 until resistance emerged. Whole genome Sequencing revealed all 17 resistant clones acquired nonsynonymous mutations in the gene encoding the orphan apicomplexan transporter PF3D7_0312500 (pfmfr3) predicted to encode a member of the major facilitator superfamily (MFS). Disruption of pfmfr3 and testing against a panel of antimalarial compounds showed decreased sensitivity to MMV085203 and GNF-Pf-3600 as well as Other compounds that have a mitochondrial mechanism of action. In contrast, mutations in pfmfr3 provided no protection against compounds that act in the food vacuole or the cytosol. A Dihydroorotate Dehydrogenase rescue assay using transgenic Parasite lines, however, indicated a different mechanism of action for both MMV085203 and GNF-Pf-3600 than the direct inhibition of cytochrome bc1. Green fluorescent protein (GFP) tagging of PfMFR3 revealed that it localizes to the Parasite mitochondrion. Our data are consistent with PfMFR3 playing roles in mitochondrial transport as well as drug resistance for clinically relevant antimalarials that target the mitochondria. Furthermore, given that pfmfr3 is naturally polymorphic, naturally occurring mutations may lead to differential sensitivity to clinically relevant compounds such as atovaquone.

Keywords

drug discovery; drug resistance; malaria; mitochondria; transporter.

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