title: Within-Host Selection of Drug Resistance in a Mouse Model Reveals Dose-Dependent Selection of Atovaquone Resistance Mutations.
abstract: The evolutionary selection of malaria parasites within an individual host plays a critical role in the emergence of drug resistance. We have compared the selection of atovaquone resistance mutants in mouse models reflecting two different causes of failure of malaria treatment, an inadequate subtherapeutic dose and an incomplete therapeutic dose. The two models are based on cycles of insufficient treatment ofPlasmodium berghei-infected mice: repeated inadequate treatment associated with a subtherapeutic dose (RIaT) (0.1 mg kg-1of body weight) and repeated incomplete treatment with a therapeutic dose (RIcT) (14.4 mg kg-1of body weight). The number of treatment cycles for the development of a stable resistance phenotype during RIaT was 2.00 ± 0.00 cycles (n= 9), which is not statistically different from that during RIcT (2.57 ± 0.85 cycles; combinedn= 14;P= 0.0591). All mutations underlying atovaquone resistance selected by RIaT (M133I, T142N, and L144S) were found to be in the Qo1 (quinone binding 1) domain of the mitochondrial cytochromebgene, in contrast to those selected by RIcT (Y268N/C, L271V, K272R, and V284F) in the Qo2 domain or its neighboring sixth transmembrane region. Exposure of mixed populations of resistant parasites from RIaT to the higher therapeutic dose of RIcT revealed further insights into the dynamics of within-host selection of resistance to antimalarial drugs. These results suggest that both inadequate subtherapeutic doses and incomplete therapeutic doses in malaria treatment pose similar threats to the emergence of drug resistance. RIcT and RIaT could be developed as useful tools to predict the potential emergence of resistance to newly introduced and less-understood antimalarials.
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia suci@eijkman.go.id smarzuki@eijkman.go.id.|Department of Physiology, University of Sumatera Utara, Medan, Indonesia.
authors.forename: Suci
authors.initials: S
authors.lastname: Nuralitha
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
authors.forename: Lydia S
authors.initials: LS
authors.lastname: Murdiyarso
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
authors.forename: Josephine E
authors.initials: JE
authors.lastname: Siregar
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
authors.forename: Din
authors.initials: D
authors.lastname: Syafruddin
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Roelands
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Verhoef
authors.affiliation: Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Andy I M
authors.initials: AIM
authors.lastname: Hoepelman
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia suci@eijkman.go.id smarzuki@eijkman.go.id.
authors.forename: Sangkot
authors.initials: S
authors.lastname: Marzuki
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D053626:Atovaquone / Q000627:therapeutic use*; D045303:Cytochromes b / Q000235:genetics*; D054796:Drug Dosage Calculations; D004351:Drug Resistance / Q000235:genetics*; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008508:Medication Errors; D051379:Mice; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei / Q000187:drug effects* / Q000235:genetics
chemical_list: D000962:Antimalarials; D045303:Cytochromes b; D053626:Atovaquone
keywords: dose-dependent selection; mouse malaria model; repeated inadequate treatment; repeated incomplete treatment; within-host selection of atovaquone resistance