Artemisinin Action and Resistance in Plasmodium falciparum.
The worldwide use of artemisinin-based combination therapies (ACTs) has contributed in recent years to a substantial reduction in deaths resulting from Plasmodium falciparum malaria. Resistance to artemisinins, however, has emerged in Southeast Asia. Clinically, resistance is defined as a slower rate of parasite clearance in patients treated with an artemisinin derivative or an ACT. These slow clearance rates associate with enhanced survival rates of ring-stage parasites briefly exposed in vitro to dihydroartemisinin. We describe recent progress made in defining the molecular basis of artemisinin resistance, which has identified a primary role for the P. falciparum K13 protein. Using K13 mutations as molecular markers, epidemiological studies are now tracking the emergence and spread of artemisinin resistance. Mechanistic studies suggest potential ways to overcome resistance.
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia. Electronic address: ltilley@unimelb.edu.au.
Leann
L
Tilley
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Judith
J
Straimer
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Nina F
NF
Gnädig
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
Stuart A
SA
Ralph
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. Electronic address: df2260@columbia.edu.
David A
DA
Fidock
D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use*; D004351:Drug Resistance / Q000235:genetics; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology*; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics
D000962:Antimalarials; D037621:Artemisinins; D015800:Protozoan Proteins
Kelch13; artemisinin resistance; malaria.; proteasome; ubiquitination; unfolded protein response