Isolation, Structure, and Biological Activities of Fellutamides C and D from an Undescribed Metulocladosporiella (Chaetothyriales) Using the Genome-Wide Candida albicans Fitness Test

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• 作者：Deming Xu ; John Ondeyka ; Guy H. Harris ; Deborah Zink ; Jennifer Nielsen Kahn ; Hao Wang ; Gerald Bills ; Gonzalo Platas ; Wenxian Wang ; Alexander A. Szewczak ; Paul Liberator ; Terry Roemer ; Sheo B. Singh
• 刊名：Journal of Natural Products
• 出版年：2011
• 出版时间：August 26, 2011
• 年：2011
• 卷：74
• 期：8
• 页码：1721-1730
• 全文大小：1024K
• 年卷期：v.74,no.8(August 26, 2011)
• ISSN：1520-6025

文摘

In a whole-cell mechanism of action (MOA)-based screening strategy for discovery of antifungal agents, Candida albicans was used, followed by testing of active extracts in the C. albicans fitness test (CaFT), which provides insight into the mechanism of action. A fermentation extract of an undescribed species of Metulocladosporiella that inhibited proteasome activity in a C. albicans fitness test was identified. The chemical genomic profile of the extract contained hypersensitivity of heterozygous deletion strains (strains that had one of the genes of the diploid genes knocked down) of genes represented by multiple subunits of the 25S proteasome. Two structurally related peptide aldehydes, named fellutamides C and D, were isolated from the extract. Fellutamides were active against C. albicans and Aspergillus fumigatus with MICs ranging from 4 to 16 渭g/mL and against fungal proteasome (IC₅₀ 0.2 渭g/mL). Both compounds showed proteasome activity against human tumor cell lines, potently inhibiting the growth of PC-3 prostate carcinoma cells, but not A549 lung carcinoma cells. In PC-3 cells compound treatment produced a G2M cell cycle block and induced apoptosis. Preliminary SAR studies indicated that the aldehyde group is critical for the antifungal activity and that the two hydroxy groups are quantitatively important for potency.