Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites

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 F2s, and identified a single QTL (LOD=31) on chromosome 6. A sulfotransferase was identified as the causative gene using RNAi 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. Overall design: mRNA profiles from adult worms resistant (HR, 3 replicates) and susceptible (LE, 2 replicates) to the oxamniquine drug were compared to identify differential expression in genes related to drug resistance

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Valentim CL, Cioli D, Chevalier FD, Cao X, Taylor AB, Holloway SP, Pica-Mattoccia L, Guidi A, Basso A, Tsai IJ, Berriman M, Carvalho-Queiroz C, Almeida M, Aguilar H, Frantz DE, Hart PJ, LoVerde PT, Anderson TJ