title: Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6.
abstract: Artemisinin derivatives are an essential component of treatment against multidrug-resistant Plasmodium falciparum malaria. We aimed to investigate in-vitro resistance to artemisinin derivatives in field isolates. In-vitro susceptibility of 530 P falciparum isolates from three countries (Cambodia, French Guiana, and Senegal) with different artemisinin use was assessed with an isotopic microtest. Artemether IC50 up to 117 and 45 nmol/L was seen in French Guiana and Senegal, respectively. DNA sequencing in a subsample of 60 isolates lends support to SERCA-PfATPase6 as the target for artemisinins. The S769N PfATPase6 mutation, noted exclusively in French Guiana, was associated with raised (>30 nmol/L) artemether IC50s (p<0.0001, Mann-Whitney). All resistant isolates came from areas with uncontrolled use of artemisinin derivatives. This rise in resistance indicates the need for increased vigilance and a coordinated and rapid deployment of drug combinations.
authors.affiliation: Unité d'Immunologie, Institut Pasteur de Dakar, BP 220, Dakar, Senegal. rjambou@pasteur.sn
authors.forename: Ronan
authors.initials: R
authors.lastname: Jambou
authors.forename: Eric
authors.initials: E
authors.lastname: Legrand
authors.forename: Makhtar
authors.initials: M
authors.lastname: Niang
authors.forename: Nimol
authors.initials: N
authors.lastname: Khim
authors.forename: Pharath
authors.initials: P
authors.lastname: Lim
authors.forename: Béatrice
authors.initials: B
authors.lastname: Volney
authors.forename: Marie Thérèse
authors.initials: MT
authors.lastname: Ekala
authors.forename: Christiane
authors.initials: C
authors.lastname: Bouchier
authors.forename: Philippe
authors.initials: P
authors.lastname: Esterre
authors.forename: Thierry
authors.initials: T
authors.lastname: Fandeur
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000077549:Artemether; D037621:Artemisinins / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005838:Genotype; D006801:Humans; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D017354:Point Mutation / Q000235:genetics*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077549:Artemether