title: Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL), a Resistance Mechanism for Two Distinct Compound Classes.
abstract: MMV007564 is a novel antimalarial benzimidazolyl piperidine chemotype identified in cellular screens. To identify the genetic determinant of MMV007564 resistance, parasites were cultured in the presence of the compound to generate resistant lines. Whole genome sequencing revealed distinct mutations in the gene named Plasmodium falciparum cyclic amine resistance locus (pfcarl), encoding a conserved protein of unknown function. Mutations in pfcarl are strongly associated with resistance to a structurally unrelated class of compounds, the imidazolopiperazines, including KAF156, currently in clinical trials. Our data demonstrate that pfcarl mutations confer resistance to two distinct compound classes, benzimidazolyl piperidines and imidazolopiperazines. However, MMV007564 and the imidazolopiperazines, KAF156 and GNF179, have different timings of action in the asexual blood stage and different potencies against the liver and sexual blood stages. These data suggest that pfcarl is a multidrug-resistance gene rather than a common target for benzimidazolyl piperidines and imidazolopiperazines.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health , Boston, Massachusetts 02115, United States.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Magistrado
authors.affiliation: School of Medicine, University of California-San Diego , La Jolla, California 92093, United States.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Corey
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health , Boston, Massachusetts 02115, United States.|Infectious Disease Program, The Broad Institute , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Lukens
authors.affiliation: School of Medicine, University of California-San Diego , La Jolla, California 92093, United States.
authors.forename: Greg
authors.initials: G
authors.lastname: LaMonte
authors.affiliation: School of Medicine, University of California-San Diego , La Jolla, California 92093, United States.
authors.forename: Erika
authors.initials: E
authors.lastname: Sasaki
authors.affiliation: School of Medicine, University of California-San Diego , La Jolla, California 92093, United States.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.affiliation: School of Medicine, University of California-San Diego , La Jolla, California 92093, United States.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wree
authors.affiliation: School of Medicine, University of California-San Diego , La Jolla, California 92093, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Winzeler
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health , Boston, Massachusetts 02115, United States.|Infectious Disease Program, The Broad Institute , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D008018:Life Cycle Stages; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D009154:Mutation; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D010880:Piperidines; D015800:Protozoan Proteins; C032727:piperidine
keywords: PfCARL; antimalarials; malaria; mutation; resistance