Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates
Judith Straimer, Nina F Gnädig, Benoit Witkowski, Chanaki Amaratunga, Valentine Duru, Arba Pramundita Ramadani, Mélanie Dacheux, Nimol Khim, Lei Zhang, Stephen Lam, Philip D Gregory, Fyodor D Urnov, Odile Mercereau-Puijalon, Françoise Benoit-Vical, Rick M Fairhurst, Didier Ménard, David A Fidock, Judith Straimer, Nina F Gnädig, Benoit Witkowski, Chanaki Amaratunga, Valentine Duru, Arba Pramundita Ramadani, Mélanie Dacheux, Nimol Khim, Lei Zhang, Stephen Lam, Philip D Gregory, Fyodor D Urnov, Odile Mercereau-Puijalon, Françoise Benoit-Vical, Rick M Fairhurst, Didier Ménard, David A Fidock
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.
Conflict of interest statement
All other authors declare no competing financial interests.
Copyright © 2015, American Association for the Advancement of Science.
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Source: PubMed