Antifungal Activity of Disalt of Epipyrone A from <i>Epicoccum nigrum</i> Likely via Disrupted Fatty Acid Elongation and Sphingolipid Biosynthesis
Multidrug-resistant fungal pathogens and antifungal drug toxicity have challenged our current ability to fight fungal infections. Therefore, there is a strong global demand for novel antifungal molecules with the distinct mode of action and specificity to service the medical and agricultural sectors...
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MDPI AG
2024-08-01
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| Series: | Journal of Fungi |
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| Online Access: | https://www.mdpi.com/2309-608X/10/9/597 |
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| author | Alex J. Lee Joseph Hammond Jeffrey Sheridan Simon Swift Andrew B. Munkacsi Silas G. Villas-Boas |
| author_facet | Alex J. Lee Joseph Hammond Jeffrey Sheridan Simon Swift Andrew B. Munkacsi Silas G. Villas-Boas |
| author_sort | Alex J. Lee |
| collection | DOAJ |
| description | Multidrug-resistant fungal pathogens and antifungal drug toxicity have challenged our current ability to fight fungal infections. Therefore, there is a strong global demand for novel antifungal molecules with the distinct mode of action and specificity to service the medical and agricultural sectors. Polyenes are a class of antifungal drugs with the broadest spectrum of activity among the current antifungal drugs. Epipyrone A, a water-soluble antifungal molecule with a unique, linear polyene structure, was isolated from the fungus <i>Epiccocum nigrum</i>. Since small changes in a compound structure can significantly alter its cell target and mode of action, we present here a study on the antifungal mode of action of the disalt of epipyrone A (DEA) using chemical-genetic profiling, fluorescence microscopy, and metabolomics. Our results suggest the disruption of sphingolipid/fatty acid biosynthesis to be the primary mode of action of DEA, followed by the intracellular accumulation of toxic phenolic compounds, in particular <i>p</i>-toluic acid (4-methylbenzoic acid). Although membrane ergosterol is known to be the main cell target for polyene antifungal drugs, we found little evidence to support that is the case for DEA. Sphingolipids, on the other hand, are known for their important roles in fungal cell physiology, and their biosynthesis has been recognized as a potential fungal-specific cell target for the development of new antifungal drugs. |
| format | Article |
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| issn | 2309-608X |
| language | English |
| publishDate | 2024-08-01 |
| publisher | MDPI AG |
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| series | Journal of Fungi |
| spelling | doaj-art-9cc4df8fb1fc433da6a5c0664d083df92025-08-20T01:55:34ZengMDPI AGJournal of Fungi2309-608X2024-08-0110959710.3390/jof10090597Antifungal Activity of Disalt of Epipyrone A from <i>Epicoccum nigrum</i> Likely via Disrupted Fatty Acid Elongation and Sphingolipid BiosynthesisAlex J. Lee0Joseph Hammond1Jeffrey Sheridan2Simon Swift3Andrew B. Munkacsi4Silas G. Villas-Boas5School of Biological Sciences, University of Auckland, Auckland 1010, New ZealandSchool of Biological Sciences, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New ZealandSchool of Biological Sciences, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New ZealandFaculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New ZealandSchool of Biological Sciences, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New ZealandSchool of Biological Sciences, University of Auckland, Auckland 1010, New ZealandMultidrug-resistant fungal pathogens and antifungal drug toxicity have challenged our current ability to fight fungal infections. Therefore, there is a strong global demand for novel antifungal molecules with the distinct mode of action and specificity to service the medical and agricultural sectors. Polyenes are a class of antifungal drugs with the broadest spectrum of activity among the current antifungal drugs. Epipyrone A, a water-soluble antifungal molecule with a unique, linear polyene structure, was isolated from the fungus <i>Epiccocum nigrum</i>. Since small changes in a compound structure can significantly alter its cell target and mode of action, we present here a study on the antifungal mode of action of the disalt of epipyrone A (DEA) using chemical-genetic profiling, fluorescence microscopy, and metabolomics. Our results suggest the disruption of sphingolipid/fatty acid biosynthesis to be the primary mode of action of DEA, followed by the intracellular accumulation of toxic phenolic compounds, in particular <i>p</i>-toluic acid (4-methylbenzoic acid). Although membrane ergosterol is known to be the main cell target for polyene antifungal drugs, we found little evidence to support that is the case for DEA. Sphingolipids, on the other hand, are known for their important roles in fungal cell physiology, and their biosynthesis has been recognized as a potential fungal-specific cell target for the development of new antifungal drugs.https://www.mdpi.com/2309-608X/10/9/597<i>Saccharomyces cerevisiae</i>mechanism of actionpolyenefungicidesphingolipidelo2 |
| spellingShingle | Alex J. Lee Joseph Hammond Jeffrey Sheridan Simon Swift Andrew B. Munkacsi Silas G. Villas-Boas Antifungal Activity of Disalt of Epipyrone A from <i>Epicoccum nigrum</i> Likely via Disrupted Fatty Acid Elongation and Sphingolipid Biosynthesis Journal of Fungi <i>Saccharomyces cerevisiae</i> mechanism of action polyene fungicide sphingolipid elo2 |
| title | Antifungal Activity of Disalt of Epipyrone A from <i>Epicoccum nigrum</i> Likely via Disrupted Fatty Acid Elongation and Sphingolipid Biosynthesis |
| title_full | Antifungal Activity of Disalt of Epipyrone A from <i>Epicoccum nigrum</i> Likely via Disrupted Fatty Acid Elongation and Sphingolipid Biosynthesis |
| title_fullStr | Antifungal Activity of Disalt of Epipyrone A from <i>Epicoccum nigrum</i> Likely via Disrupted Fatty Acid Elongation and Sphingolipid Biosynthesis |
| title_full_unstemmed | Antifungal Activity of Disalt of Epipyrone A from <i>Epicoccum nigrum</i> Likely via Disrupted Fatty Acid Elongation and Sphingolipid Biosynthesis |
| title_short | Antifungal Activity of Disalt of Epipyrone A from <i>Epicoccum nigrum</i> Likely via Disrupted Fatty Acid Elongation and Sphingolipid Biosynthesis |
| title_sort | antifungal activity of disalt of epipyrone a from i epicoccum nigrum i likely via disrupted fatty acid elongation and sphingolipid biosynthesis |
| topic | <i>Saccharomyces cerevisiae</i> mechanism of action polyene fungicide sphingolipid elo2 |
| url | https://www.mdpi.com/2309-608X/10/9/597 |
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