title: Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in western Cambodia.
abstract: The declining efficacy of artemisinin derivatives against Plasmodium falciparum in western Cambodia is a major concern. The knowledge gap in the understanding of the mechanisms involved hampers designing monitoring tools. Here, we culture-adapted 20 isolates from Pailin and Ratanakiri (areas of artemisinin resistance and susceptibility in western and eastern Cambodia, respectively) and studied their in vitro response to dihydroartemisinin. No significant difference between the two sets of isolates was observed in the classical isotopic test. However, a 6-h pulse exposure to 700 nM dihydroartemisinin (ring-stage survival assay -RSA]) revealed a clear-cut geographic dichotomy. The survival rate of exposed ring-stage parasites (ring stages) was 17-fold higher in isolates from Pailin (median, 13.5%) than in those from Ratanakiri (median, 0.8%), while exposed mature stages were equally and highly susceptible (0.6% and 0.7%, respectively). Ring stages survived drug exposure by cell cycle arrest and resumed growth upon drug withdrawal. The reduced susceptibility to artemisinin in Pailin appears to be associated with an altered in vitro phenotype of ring stages from Pailin in the RSA.
authors.affiliation: Malaria Molecular Epidemiology Unit, Institut Pasteur in Cambodia, Phnom Penh, Cambodia.
authors.forename: Benoit
authors.initials: B
authors.lastname: Witkowski
authors.forename: Nimol
authors.initials: N
authors.lastname: Khim
authors.forename: Pheaktra
authors.initials: P
authors.lastname: Chim
authors.forename: Saorin
authors.initials: S
authors.lastname: Kim
authors.forename: Sopheakvatey
authors.initials: S
authors.lastname: Ke
authors.forename: Nimol
authors.initials: N
authors.lastname: Kloeung
authors.forename: Sophy
authors.initials: S
authors.lastname: Chy
authors.forename: Socheat
authors.initials: S
authors.lastname: Duong
authors.forename: Rithea
authors.initials: R
authors.lastname: Leang
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.forename: Rupam
authors.initials: R
authors.lastname: Tripura
authors.forename: Françoise
authors.initials: F
authors.lastname: Benoit-Vical
authors.forename: Antoine
authors.initials: A
authors.lastname: Berry
authors.forename: Olivier
authors.initials: O
authors.lastname: Gorgette
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ariey
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Barale
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.forename: Didier
authors.initials: D
authors.lastname: Menard
mesh_terms: D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D002160:Cambodia; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004351:Drug Resistance; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C039060:artenimol