title: Artemisinin-resistant Plasmodium falciparum parasites exhibit altered patterns of development in infected erythrocytes.
abstract: Artemisinin derivatives are used in combination with other antimalarial drugs for treatment of multidrug-resistant malaria worldwide. Clinical resistance to artemisinin recently emerged in southeast Asia, yet in vitro phenotypes for discerning mechanism(s) of resistance remain elusive. Here, we describe novel phenotypic resistance traits expressed by artemisinin-resistant Plasmodium falciparum. The resistant parasites exhibit altered patterns of development that result in reduced exposure to drug at the most susceptible stage of development in erythrocytes (trophozoites) and increased exposure in the most resistant stage (rings). In addition, a novel in vitro delayed clearance assay (DCA) that assesses drug effects on asexual stages was found to correlate with parasite clearance half-life in vivo as well as with mutations in the Kelch domain gene associated with resistance (Pf3D7_1343700). Importantly, all of the resistance phenotypes were stable in cloned parasites for more than 2 years without drug pressure. The results demonstrate artemisinin-resistant P. falciparum has evolved a novel mechanism of phenotypic resistance to artemisinin drugs linked to abnormal cell cycle regulation. These results offer insights into a novel mechanism of drug resistance in P. falciparum and new tools for monitoring the spread of artemisinin resistance.
authors.affiliation: Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Hott
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, USA.
authors.forename: Debora
authors.initials: D
authors.lastname: Casandra
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, USA.
authors.forename: Kansas N
authors.initials: KN
authors.lastname: Sparks
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, USA.
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Morton
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, USA.
authors.forename: Geocel-Grace
authors.initials: GG
authors.lastname: Castanares
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Rutter
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, USA dkyle@health.usf.edu.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
mesh_terms: D000981:Antiprotozoal Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002478:Cells, Cultured; D004351:Drug Resistance; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D019271:Hypoxanthine / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000472:pathogenicity; D020641:Polymorphism, Single Nucleotide
chemical_list: D000981:Antiprotozoal Agents; D037621:Artemisinins; D019271:Hypoxanthine; C031327:artemisinin