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

Claudia L.L. Valentim, Donato Cioli, Fréd́eric 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

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1385-1389
Number of pages5
JournalScience
Volume342
Issue number6164
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • General

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