title: 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.affiliation: Evolva SA, Reinach, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Knechtle
authors.forename: Melanie
authors.initials: M
authors.lastname: Diefenbacher
authors.forename: Katrine B V
authors.initials: KB
authors.lastname: Greve
authors.forename: Federico
authors.initials: F
authors.lastname: Brianza
authors.forename: Christophe
authors.initials: C
authors.lastname: Folly
authors.forename: Harald
authors.initials: H
authors.lastname: Heider
authors.forename: Museer A
authors.initials: MA
authors.lastname: Lone
authors.forename: Lisa
authors.initials: L
authors.lastname: Long
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Meyer
authors.forename: Patrick
authors.initials: P
authors.lastname: Roussel
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Ghannoum
authors.forename: Roger
authors.initials: R
authors.lastname: Schneiter
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Sorensen
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D044943:Fatty Acid Desaturases / Q000037:antagonists & inhibitors*; D015971:Gene Expression Regulation, Enzymologic; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D006168:Guinea Pigs; D013230:Stearoyl-CoA Desaturase; D014005:Tinea / Q000188:drug therapy*
chemical_list: D000935:Antifungal Agents; D044943:Fatty Acid Desaturases; D013230:Stearoyl-CoA Desaturase; C029627:delta-9 fatty acid desaturase