1. The Discovery of Weddellamycin, a Tricyclic Polyene Macrolactam Antibiotic from an Antarctic Deep-Sea-Derived Streptomyces sp. DSS69, by Heterologous Expression.
- Author
-
Chen L, Liu K, Hong J, Cui Z, He W, Wang Y, Deng Z, and Tao M
- Subjects
- Humans, Polyenes pharmacology, Polyenes isolation & purification, Polyenes chemistry, Candida albicans drug effects, Cell Line, Tumor, Antarctic Regions, Animals, Porifera microbiology, Antifungal Agents pharmacology, Antifungal Agents chemistry, Antifungal Agents isolation & purification, Streptomyces genetics, Streptomyces metabolism, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents biosynthesis, Anti-Bacterial Agents chemistry, Lactams, Macrocyclic pharmacology, Lactams, Macrocyclic chemistry, Lactams, Macrocyclic isolation & purification, Microbial Sensitivity Tests, Multigene Family
- Abstract
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 IC
50 values ranging from 2.07 to 11.50 µM.- Published
- 2024
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