title: Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates.
abstract: The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites.
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Straimer
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Nina F
authors.initials: NF
authors.lastname: Gnädig
authors.affiliation: Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Benoit
authors.initials: B
authors.lastname: Witkowski
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Chanaki
authors.initials: C
authors.lastname: Amaratunga
authors.affiliation: Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Valentine
authors.initials: V
authors.lastname: Duru
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie de Coordination UPR8241, Toulouse, France. Université de Toulouse, UPS, Institut National Polytechnique de Toulouse, Toulouse, France.
authors.forename: Arba Pramundita
authors.initials: AP
authors.lastname: Ramadani
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Dacheux
authors.affiliation: Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Nimol
authors.initials: N
authors.lastname: Khim
authors.affiliation: Sangamo BioSciences, Richmond, CA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Sangamo BioSciences, Richmond, CA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.affiliation: Sangamo BioSciences, Richmond, CA, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Gregory
authors.affiliation: Sangamo BioSciences, Richmond, CA, USA.
authors.forename: Fyodor D
authors.initials: FD
authors.lastname: Urnov
authors.affiliation: Institut Pasteur, Parasite Molecular Immunology Unit, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie de Coordination UPR8241, Toulouse, France. Université de Toulouse, UPS, Institut National Polytechnique de Toulouse, Toulouse, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Benoit-Vical
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
authors.affiliation: Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Didier
authors.initials: D
authors.lastname: Ménard
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA. Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA. df2260@columbia.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002160:Cambodia; D004351:Drug Resistance / Q000235:genetics*; D056426:Genetic Loci; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008969:Molecular Sequence Data; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D015800:Protozoan Proteins; C031327:artemisinin