Genetic and molecular basis of drug resistance and species-specific drug action in schistosome parasites.
Science
; 342(6164): 1385-9, 2013 Dec 13.
Article
em En
| MEDLINE
| ID: mdl-24263136
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oxamniquine
/
Schistosoma mansoni
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Esquistossomicidas
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Resistência a Medicamentos
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Sulfotransferases
/
Proteínas de Helminto
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos