期刊
SCIENCE
卷 342, 期 6164, 页码 1385-1389出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1243106
关键词
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资金
- NIH [5R21-AI096277, 5R21-AI072704, R01-AI097576]
- World Health Organization [HQNTD1206356]
- Research Facilities Improvement Program Grant from National Center for Research Resources (NIH) [C06 RR013556]
- Wellcome Trust [098051]
- Robert A. Welch Foundation [AQ-1399]
- NIH-National Institute of Allergy and Infectious Diseases [HHSN272201000005I]
- University of Texas Health Science Center, San Antonio, Office of the Vice President for Research
Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing similar to 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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