title: Genomewide scan reveals amplification of mdr1 as a common denominator of resistance to mefloquine, lumefantrine, and artemisinin in Plasmodium chabaudi malaria parasites.
abstract: Multidrug-resistant Plasmodium falciparum malaria parasites pose a threat to effective drug control, even to artemisinin-based combination therapies (ACTs). Here we used linkage group selection and Solexa whole-genome resequencing to investigate the genetic basis of resistance to component drugs of ACTs. Using the rodent malaria parasite P. chabaudi, we analyzed the uncloned progeny of a genetic backcross between the mefloquine-, lumefantrine-, and artemisinin-resistant mutant AS-15MF and a genetically distinct sensitive clone, AJ, following drug treatment. Genomewide scans of selection showed that parasites surviving each drug treatment bore a duplication of a segment of chromosome 12 (translocated to chromosome 04) present in AS-15MF. Whole-genome resequencing identified the size of the duplicated segment and its position on chromosome 4. The duplicated fragment extends for ∼393 kbp and contains over 100 genes, including mdr1, encoding the multidrug resistance P-glycoprotein homologue 1. We therefore show that resistance to chemically distinct components of ACTs is mediated by the same genetic mutation, highlighting a possible limitation of these therapies.
authors.affiliation: UEI Malária, Centro de Malária e Outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira no. 100, 1349-008 Lisbon, Portugal. sofiaborges@hotmail.com
authors.forename: Sofia
authors.initials: S
authors.lastname: Borges
authors.forename: Pedro
authors.initials: P
authors.lastname: Cravo
authors.forename: Alison
authors.initials: A
authors.lastname: Creasey
authors.forename: Richard
authors.initials: R
authors.lastname: Fawcett
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Modrzynska
authors.forename: Louise
authors.initials: L
authors.lastname: Rodrigues
authors.forename: Axel
authors.initials: A
authors.lastname: Martinelli
authors.forename: Paul
authors.initials: P
authors.lastname: Hunt
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D001483:Base Sequence; D002874:Chromosome Mapping; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004983:Ethanolamines / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D008040:Genetic Linkage; D018503:Genome, Protozoan; D000078102:Lumefantrine; D008288:Malaria / Q000188:drug therapy*; D015767:Mefloquine / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D016788:Plasmodium chabaudi / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D000078102:Lumefantrine; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C031327:artemisinin