Isolation, Structure, and Biological Activity of Phaeofungin, a Cyclic Lipodepsipeptide from a Phaeosphaeria sp. Using the Genome-Wide Candida albicans Fitness Test

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• 作者：Sheo B. Singh ; John Ondeyka ; Guy Harris ; Kithsiri Herath ; Deborah Zink ; Francisca Vicente ; Gerald Bills ; Javier Collado ; Gonzalo Platas ; Antonio Gonz谩lez del Val ; Jesus Martin ; Fernando Reyes ; Hao Wang ; Jennifer Nielsen Kahn ; Stefan Galuska ; Robert Giacobbe ; George Abruzzo ; Terry Roemer ; Deming Xu
• 刊名：Journal of Natural Products
• 出版年：2013
• 出版时间：March 22, 2013
• 年：2013
• 卷：76
• 期：3
• 页码：334-345
• 全文大小：733K
• 年卷期：v.76,no.3(March 22, 2013)
• ISSN：1520-6025

文摘

Phaeofungin (1), a new cyclic depsipeptide isolated from Phaeosphaeria sp., was discovered by application of reverse genetics technology, using the Candida albicans fitness test (CaFT). Phaeofungin is comprised of seven amino acids and a 尾,纬-dihydroxy-纬-methylhexadecanoic acid arranged in a 25-membered cyclic depsipeptide. Five of the amino acids were assigned with d-configurations. The structure was elucidated by 2D-NMR and HRMS-MS analysis of the natural product and its hydrolyzed linear peptide. The absolute configuration of the amino acids was determined by Marfey鈥檚 method by complete and partial hydrolysis of 1. The CaFT profile of the phaeofungin-containing extract overlapped with that of phomafungin (3), another structurally different cyclic lipodepsipeptide isolated from a Phoma sp. using the same approach. Comparative biological characterization further demonstrated that these two fungal lipodepsipeptides are functionally distinct. While phomafungin was potentiated by cyclosporin A (an inhibitor of the calcineurin pathway), phaeofungin was synergized with aureobasidin A (2) (an inhibitor of the sphingolipid biosynthesis) and to some extent caspofungin (an inhibitor of glucan synthase). Furthermore, phaeofungin caused ATP release in wild-type C. albicans strains but phomafungin did not. It showed modest antifungal activity against C. albicans (MIC 16鈥?2 渭g/mL) and better activity against Aspergillus fumigatus (MIC 8鈥?6 渭g/mL) and Trichophyton mentagrophytes (MIC 4 渭g/mL). The linear peptide was inactive, suggesting that the macrocyclic depsipeptide ring is essential for target engagement and antifungal activity.