多烯大分子内酰胺是一类特殊的天然产物，具有很大的多样性，独特的结构特征，和广泛的生物活性。在这里，从海绵相关细菌中公开了一种用于生物合成推定的大分子内酰胺的隐蔽基因簇，链霉菌sp.DSS69，通过基因组挖掘。整个生物合成基因簇的克隆和异源表达导致了韦德霉素的发现，具有23/5/6环骨架的多烯大内酰胺。负调节器，WdlO,和两个正调节器，WdlA和WdlB,参与调节weddellamycin的生产被解开。wdlA和wdlB的过表达和wdlO的缺失显著提高了weddellamycin的发酵滴度。值得注意的是,韦德霉素对包括MRSA在内的各种革兰氏阳性细菌显示出显着的抗菌活性，MIC值为0.10-0.83μg/mL，和抗白念珠菌的抗真菌活性，MIC值为3.33μg/mL。Wedellamycin还显示出对几种癌细胞系的细胞毒性，IC50值范围为2.07至11.50µM。
Polyene macrolactams are a special group of natural products with great diversity, unique structural features, and a wide range of biological activities. Herein, a cryptic gene cluster for the biosynthesis of putative macrolactams was disclosed from a sponge-associated bacterium, Streptomyces sp. DSS69, by genome mining. Cloning and heterologous expression of the whole biosynthetic gene cluster led to the discovery of weddellamycin, a polyene macrolactam bearing a 23/5/6 ring skeleton. A negative regulator, WdlO, and two positive regulators, WdlA and WdlB, involved in the regulation of weddellamycin production were unraveled. The fermentation titer of weddellamycin was significantly improved by overexpression of wdlA and wdlB and deletion of wdlO. Notably, weddellamycin showed remarkable antibacterial activity against various Gram-positive bacteria including MRSA, with MIC values of 0.10-0.83 μg/mL, and antifungal activity against Candida albicans, with an MIC value of 3.33 μg/mL. Weddellamycin also displayed cytotoxicity against several cancer cell lines, with IC50 values ranging from 2.07 to 11.50 µM.
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