1. Genetic and molecular basis of drug resistance and species-specific drug action in schistosome parasites.
- Author
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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, and Anderson TJ
- Subjects
- Amino Acid Sequence, Animals, Gene Knockdown Techniques, Genetic Linkage, Humans, Molecular Sequence Data, Mutation, Phylogeny, Protein Conformation, Quantitative Trait Loci, RNA Interference, Sulfotransferases chemistry, Sulfotransferases classification, Drug Resistance genetics, Helminth Proteins genetics, Oxamniquine pharmacology, Schistosoma mansoni drug effects, Schistosoma mansoni genetics, Schistosomicides pharmacology, Sulfotransferases genetics
- 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.
- Published
- 2013
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