K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates

Judith Straimer (1) , Nina F. Gnadig (1) , Benoit Witkowski (2) , Chanaki Amaratunga (3) , Valentine Duru (2) , Arba Pramundita Ramadani (4, 5) , Mélanie Dacheux (1) , Nimol Khim (2) , Lei Zhang (6) , Stephen Lam (6) , Philip D. Gregory (6) , Fyodor D. Urnov (6) , O. Mercereau-Puijalon (7) , Françoise Benoit-Vical (4, 5) , Rick M. Fairhurst (3) , Didier Menard (2) , David A. Fidock (1)

1 Columbia University College of Physicians and Surgeons
2 Institut Pasteur du Cambodge
3 NIH - National Institutes of Health [Bethesda, MD, USA]
4 LCC - Laboratoire de chimie de coordination
5 UT3 - Université Toulouse III - Paul Sabatier
6 Sangamo BioSciences
7 Immunologie Moléculaire des Parasites

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.

Domaines: Chimie de coordination

Judith Straimer, Nina F. Gnadig, Benoit Witkowski, Chanaki Amaratunga, Valentine Duru, et al.. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science, 2015, 347 (6220), pp.428-431. ⟨10.1126/science.1260867⟩. ⟨hal-01925134⟩