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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.

Original publication

DOI

10.1126/science.1260867

Type

Journal article

Journal

Science (New York, N.Y.)

Publication Date

01/2015

Volume

347

Pages

428 - 431

Addresses

Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA.

Keywords

Humans, Plasmodium falciparum, Malaria, Falciparum, Artemisinins, Protozoan Proteins, Antimalarials, Amino Acid Sequence, Protein Structure, Tertiary, Drug Resistance, Mutation, Molecular Sequence Data, Cambodia, Genetic Loci