title: Genetic and molecular basis of drug resistance and species-specific drug action in schistosome parasites.
abstract: Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.
authors.affiliation: Departments of Biochemistry and Pathology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Claudia L L
authors.initials: CL
authors.lastname: Valentim
authors.forename: Donato
authors.initials: D
authors.lastname: Cioli
authors.forename: Frédéric D
authors.initials: FD
authors.lastname: Chevalier
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Cao
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Taylor
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Holloway
authors.forename: Livia
authors.initials: L
authors.lastname: Pica-Mattoccia
authors.forename: Alessandra
authors.initials: A
authors.lastname: Guidi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Basso
authors.forename: Isheng J
authors.initials: IJ
authors.lastname: Tsai
authors.forename: Matthew
authors.initials: M
authors.lastname: Berriman
authors.forename: Claudia
authors.initials: C
authors.lastname: Carvalho-Queiroz
authors.forename: Marcio
authors.initials: M
authors.lastname: Almeida
authors.forename: Hector
authors.initials: H
authors.lastname: Aguilar
authors.forename: Doug E
authors.initials: DE
authors.lastname: Frantz
authors.forename: P John
authors.initials: PJ
authors.lastname: Hart
authors.forename: Philip T
authors.initials: PT
authors.lastname: LoVerde
authors.forename: Timothy J C
authors.initials: TJ
authors.lastname: Anderson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004351:Drug Resistance / Q000235:genetics*; D055785:Gene Knockdown Techniques; D008040:Genetic Linkage; D015801:Helminth Proteins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010073:Oxamniquine / Q000494:pharmacology*; D010802:Phylogeny; D011487:Protein Conformation; D040641:Quantitative Trait Loci; D034622:RNA Interference; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000235:genetics*; D012556:Schistosomicides / Q000494:pharmacology*; D015238:Sulfotransferases / Q000737:chemistry / Q000145:classification / Q000235:genetics*
chemical_list: D015801:Helminth Proteins; D012556:Schistosomicides; D010073:Oxamniquine; D015238:Sulfotransferases