| Autor: |
Knechtle, Philipp, Diefenbacher, Melanie, Greve, Katrine B. V., Brianza, Federico, Folly, Christophe, Heider, Harald, Lone, Museer A., Long, Lisa, Meyer, Jean-Philippe, Roussel, Patrick, Ghannoum, Mahmoud A., Schneiter, Roger, Sorensen, Alexandra S. |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; November 2013, Vol. 58 Issue: 1 p455-466, 12p |
| Abstrakt: |
ABSTRACTHuman fungal infections represent a therapeutic challenge. Although effective strategies for treatment are available, resistance is spreading, and many therapies have unacceptable side effects. A clear need for novel antifungal targets and molecules is thus emerging. Here, we present the identification and characterization of the plant-derived diyne-furan fatty acid EV-086 as a novel antifungal compound. EV-086 has potent and broad-spectrum activity in vitroagainst Candida, Aspergillus, and Trichophytonspp., whereas activities against bacteria and human cell lines are very low. Chemical-genetic profiling of Saccharomyces cerevisiaedeletion mutants identified lipid metabolic processes and organelle organization and biogenesis as targets of EV-086. Pathway modeling suggested that EV-086 inhibits delta-9 fatty acid desaturation, an essential process in S. cerevisiae, depending on the delta-9 fatty acid desaturase OLE1. Delta-9 unsaturated fatty acids—but not saturated fatty acids—antagonized the EV-086-mediated growth inhibition, and transcription of the OLE1gene was strongly upregulated in the presence of EV-086. EV-086 increased the ratio of saturated to unsaturated free fatty acids and phosphatidylethanolamine fatty acyl chains, respectively. Furthermore, EV-086 was rapidly taken up into the lipid fraction of the cell and incorporated into phospholipids. Together, these findings demonstrate that EV-086 is an inhibitor of delta-9 fatty acid desaturation and that the mechanism of inhibition might involve an EV-086–phospholipid. Finally, EV-086 showed efficacy in a guinea pig skin dermatophytosis model of topical Trichophytoninfection, which demonstrates that delta-9 fatty acid desaturation is a valid antifungal target, at least for dermatophytoses. |
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