原创力文档a molecular mechanism for eflornithine resistance in african trypanosomes在非洲锥虫依氟鸟氨酸抗性的分子机制.pdfVIP
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a molecular mechanism for eflornithine resistance in african trypanosomes在非洲锥虫依氟鸟氨酸抗性的分子机制
A Molecular Mechanism for Eflornithine Resistance in
African Trypanosomes
1 1 2 2¤ 3
Isabel M. Vincent , Darren Creek , David G. Watson , Mohammed A. Kamleh , Debra J. Woods , Pui Ee
1 1 1
Wong , Richard J. S. Burchmore , Michael P. Barrett *
1 Faculty of Biomedical and Life Science and Wellcome Trust Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow,
United Kingdom, 2 Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom, 3 Pfizer Animal Health, Pfizer Inc,
Kalamazoo, Michigan, United States of America
Abstract
Human African trypanosomiasis, endemic to sub-Saharan Africa, is invariably fatal if untreated. Its causative agent is the
protozoan parasite Trypanosoma brucei. Eflornithine is used as a first line treatment for human African trypanosomiasis, but
there is a risk that resistance could thwart its use, even when used in combination therapy with nifurtimox. Eflornithine
resistant trypanosomes were selected in vitro and subjected to biochemical and genetic analysis. The resistance phenotype
was verified in vivo. Here we report the molecular basis of resistance. While the drug’s target, ornithine decarboxylase, was
unaltered in resistant cells and changes to levels of metabolites in the targeted polyamine pathway were not apparent, the
accumulation of eflornithine was shown to be diminished in resistant lines. An amino acid transporter gene, TbAAT6
(Tb927.8.5450), was found to be deleted in two lines independently selected for resistance. Ablating expression of this gene
in wildtype cells using RNA in
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