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. 2014-01-01 Human 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 vitro against Candida, Aspergillus, and Trichophyton spp., whereas activities against bacteria and human cell lines are very low. Chemical-genetic profiling of Saccharomyces cerevisiae deletion 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 OLE1 gene 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 Trichophyton infection, which demonstrates that delta-9 fatty acid desaturation is a valid antifungal target, at least for dermatophytoses. application/pdf https://folia.unifr.ch/global/documents/303516 https://folia.unifr.ch/documents/303516/files/sch_ndf.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1128/AAC.01443-13 info:eu-repo/semantics/openAccess License undefined Antimicrobial Agents and Chemotherapy. - 2013, vol. 58, no. 1, p. 455–466 info:eu-repo/classification/udc/615 The natural diyne-furan fatty acid EV-086 is an inhibitor of fungal delta-9 fatty acid desaturation with efficacy in a model of skin dermatophytosis http://purl.org/coar/resource_type/c_6501