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

• DOI: 10.1128/aac.01443-13
• Publication Date: 2013-11-05T04:07:25Z
• Authors: Philipp Knechtle; Melanie Diefenbacher; Katrine B. V. Greve; Federico Brianza; Christophe Folly; Harald Heider; Museer A. Lone; Lisa Long; Jean-Philippe Meyer; Patrick Roussel; Mahmoud A. Ghannoum; Roger Schneiter; Alexandra S. Sore...
• Keywords: Furan

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 novel antifungal targets molecules thus emerging. Here, we present the identification characterization of plant-derived diyne-furan fatty acid EV-086 as compound. has potent broad-spectrum activity in vitro against Candida, Aspergillus, Trichophyton spp., whereas activities bacteria human cell lines very low. Chemical-genetic profiling Saccharomyces cerevisiae deletion mutants identified lipid metabolic processes organelle organization biogenesis EV-086. Pathway modeling suggested that inhibits delta-9 desaturation, an essential process S. cerevisiae, depending on desaturase OLE1. Delta-9 unsaturated acids-but not saturated acids-antagonized EV-086-mediated growth inhibition, transcription OLE1 gene was strongly upregulated presence increased ratio to free acids phosphatidylethanolamine acyl chains, respectively. Furthermore, rapidly taken up into fraction incorporated phospholipids. Together, these findings demonstrate inhibitor desaturation mechanism inhibition might involve EV-086-phospholipid. Finally, showed efficacy guinea pig skin dermatophytosis model topical infection, which demonstrates valid target, at least dermatophytoses.