Knechtle P~Sorensen AS, 2014

Pubmed ID 24189258
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.
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
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.
Citation Antimicrob. Agents Chemother. 2014; 58:455-66

Datasets

Download the list of datasets
Paper Phenotype Condition Medium Collection Tested mutants Data Details
Knechtle P~Sorensen AS, 2014 growth (colony size) pomecin A [0.5-8 ug/ml] YPD hom ~4,917 Discrete

Curation history

Data

June 21, 2020 Waiting for tested.
June 22, 2020 Loaded.
June 22, 2020 Ready to load.

Tested strains

June 21, 2020 Request sent.
June 21, 2020 To request.
June 22, 2020 Not available.