title: Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure.
abstract: Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy.
authors.forename: Sandie
authors.initials: S
authors.lastname: Ménard
authors.forename: Tanila
authors.initials: T
authors.lastname: Ben Haddou
authors.forename: Arba Pramundita
authors.initials: AP
authors.lastname: Ramadani
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ariey
authors.forename: Xavier
authors.initials: X
authors.lastname: Iriart
authors.forename: Johann
authors.initials: J
authors.lastname: Beghain
authors.forename: Christiane
authors.initials: C
authors.lastname: Bouchier
authors.forename: Benoit
authors.initials: B
authors.lastname: Witkowski
authors.forename: Antoine
authors.initials: A
authors.lastname: Berry
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.forename: Françoise
authors.initials: F
authors.lastname: Benoit-Vical
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D001210:Asia, Southeastern; D004361:Drug Tolerance / Q000276:immunology*; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin
keywords: Plasmodium falciparum; Southeast Asia; antifolate; antimicrobial resistance; artemisinin; atovaquone; drug pressure; malaria; multidrug tolerance; parasites; quinolone