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.

Abstract

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.

• 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 Sorensen
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 1 Pg. 455-66 ( 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 24189258 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• Fatty Acid Desaturases
• Stearoyl-CoA Desaturase
• delta-9 fatty acid desaturase

Topics

• Animals
• Antifungal Agents (therapeutic use)
• Fatty Acid Desaturases (antagonists & inhibitors)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Fungal (drug effects)
• Guinea Pigs
• Stearoyl-CoA Desaturase
• Tinea (drug therapy)