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Genetic and molecular basis of drug resistance and species-specific drug action in schistosome parasites. 2013
Claudia L L Valentim, and
Donato Cioli, and
Frédéric D Chevalier, and
Xiaohang Cao, and
Alexander B Taylor, and
Stephen P Holloway, and
Livia Pica-Mattoccia, and
Alessandra Guidi, and
Annalisa Basso, and
Isheng J Tsai, and
Matthew Berriman, and
Claudia Carvalho-Queiroz, and
Marcio Almeida, and
Hector Aguilar, and
Doug E Frantz, and
P John Hart, and
Philip T LoVerde, and
Timothy J C Anderson
Departments of Biochemistry and Pathology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
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.
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