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High-Resolution Genetics Identifies the Lipid Transfer Protein Sec14p as Target for Antifungal Ergolines
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نویسنده
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filipuzzi i. ,cotesta s. ,perruccio f. ,knapp b. ,fu y. ,studer c. ,pries v. ,riedl r. ,helliwell s.b. ,petrovic k.t. ,movva n.r. ,sanglard d. ,tao j. ,hoepfner d.
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منبع
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plos genetics - 2016 - دوره : 12 - شماره : 11
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چکیده
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Invasive infections by fungal pathogens cause more deaths than malaria worldwide. we found the ergoline compound ngx04 in an antifungal screen,with selectivity over mammalian cells. high-resolution chemogenomics identified the lipid transfer protein sec14p as the target of ngx04 and compound-resistant mutations in sec14p define compound-target interactions in the substrate binding pocket of the protein. beyond its essential lipid transfer function in a variety of pathogenic fungi,sec14p is also involved in secretion of virulence determinants essential for the pathogenicity of fungi such as cryptococcus neoformans,making sec14p an attractive antifungal target. consistent with this dual function,we demonstrate that ngx04 inhibits the growth of two clinical isolates of c. neoformans and that ngx04-related compounds have equal and even higher potency against c. neoformans. furthermore ngx04 analogues showed fungicidal activity against a fluconazole resistant c. neoformans strain. in summary,we present genetic evidence that ngx04 inhibits fungal sec14p and initial data supporting ngx04 as a novel antifungal starting point. © 2016 filipuzzi et al.
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آدرس
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novartis institutes for biomedical research,novartis campus,basel, Switzerland, novartis institutes for biomedical research,novartis campus,basel, Switzerland, novartis institutes for biomedical research,novartis campus,basel, Switzerland, novartis institutes for biomedical research,novartis campus,basel, Switzerland, genomics institute of the novartis research foundation,san diego,ca, United States, novartis institutes for biomedical research,novartis campus,basel, Switzerland, novartis institutes for biomedical research,novartis campus,basel, Switzerland, novartis institutes for biomedical research,novartis campus,basel, Switzerland, novartis institutes for biomedical research,novartis campus,basel, Switzerland, novartis institutes for biomedical research,novartis campus,basel, Switzerland, novartis institutes for biomedical research,novartis campus,basel, Switzerland, institute of microbiology,university of lausanne and university hospital center,lausanne, Switzerland, genomics institute of the novartis research foundation,san diego,ca, United States, novartis institutes for biomedical research,novartis campus,basel, Switzerland
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Authors
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