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
- Knechtle, Philipp Evolva SA, Reinach, Switzerland
- Diefenbacher, Melanie Evolva SA, Reinach, Switzerland
- Greve, Katrine B. V. Evolva SA, Reinach, Switzerland
- Brianza, Federico Evolva SA, Reinach, Switzerland
- Folly, Christophe Evolva SA, Reinach, Switzerland
- Heider, Harald Evolva SA, Reinach, Switzerland
- Lone, Museer A. Department of Biology, Division of Biochemistry, University of Fribourg, Switzerland
- Long, Lisa Center for Medical Mycology, University Hospitals of Cleveland, Ohio, USA
- Meyer, Jean-Philippe Evolva SA, Reinach, Switzerland
- Roussel, Patrick Evolva SA, Reinach, Switzerland
- Ghannoum, Mahmoud A. Center for Medical Mycology, University Hospitals of Cleveland, Ohio, USA
- Schneiter, Roger Department of Biology, Division of Biochemistry, University of Fribourg, Switzerland
- Sorensen, Alexandra S. Evolva SA, Reinach, Switzerland
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01.01.2014
Published in:
- Antimicrobial Agents and Chemotherapy. - 2013, vol. 58, no. 1, p. 455–466
English
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.
- Faculty
- Faculté des sciences et de médecine
- Department
- Département de Biologie
- Language
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- English
- Classification
- Pharmacology, therapeutics, toxicology
- License
- License undefined
- Identifiers
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- RERO DOC 209172
- DOI 10.1128/AAC.01443-13
- Persistent URL
- https://folia.unifr.ch/unifr/documents/303516
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