High-Resolution Genetics Identifies the Lipid Transfer Protein Sec14p as Target for Antifungal Ergolines.
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- doi: 10.1371/journal.pgen.1006374
- issn: 1553-7390
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Therapy Protein conformation Debaryomyces neoformans hominis Cryptococcus hystolyticus Cryptococcus hominis Torula histolytica Cryptococcus meningitidis Treatments for diseases Medical treatment Therapy Treatment of diseases Antimicrobial sensitivity tests Susceptibility tests, Microbial Bacterial sensitivity tests Antimicrobial susceptibility tests Microbial susceptibility tests Sensitivity tests, Microbial Sensitivity tests (Microbiology) Antibiotic sensitivity tests Micro-organisms, Pathogenic Disease-causing microorganisms Pathogens People Man Humanity (Human beings) Human race Mankind Homo sapiens Humankind Humans Ague Chills and fever Intermittent fever Malarial fever Fungi, Pathogenic Funguses Fungus kingdom Fungal kingdom Mycobiota Mycota Proof Resultants Genomes--Effect of chemicals on Chemical genomics mortsCiter ce document
I. Filipuzzi et al., « High-Resolution Genetics Identifies the Lipid Transfer Protein Sec14p as Target for Antifungal Ergolines. », Serveur académique Lausannois, ID : 10.1371/journal.pgen.1006374
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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.