Genetic and Molecular Basis of Drug Resistance and Species-Specific Drug Action in Schistosome Parasites
Year: 2013
Type: article
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.
Source: Science
Authors: Claudia L. L. Valentim, Donato Cioli, Frédéric D. Chevalier, Xiaohang Cao, Alexander B. Taylor, Stephen P. Holloway, Livia Pica-Mattoccia, Alessandra Guidi, Annalisa Basso, Isheng J. Tsai, Matthew Berriman, Claudia Carvalho-Queiroz, Marcio Almeida, Hector Aguilar, Doug E. Frantz, P. John Hart, Philip T. LoVerde, Timothy J. C. Anderson
Language: English
Subfield: Parasitology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G2169778925, A Linkage Map for Schistosoma mansoni, MOLECULAR AND BIOCHEMICAL GENETICS LABORATORY RENOVATION, Genetic Analysis of Host Specificity in Schistosoma mansoni, Efficient Linkage Mapping Methods for Schistosoma mansoni, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers
OpenAlex ID: W2065594536