Activation and discovery of tsukubarubicin from Streptomyces tsukubaensis through overexpressing SARPs

• Published in: Applied microbiology and biotechnology 2021-06, Vol.105 (11), p.4731-4741
• Main Authors: Wu, Qing-Bin, Chen, Xin-Ai, Lv, Zhong-Yuan, Zhang, Xiao-Ying, Liu, Yu, Li, Yong-Quan
• Format: Article
• Language: English
• Subjects: Annotations; Anthracycline; Antibiotics; Antimitotic agents; Antineoplastic agents; Applied Microbial and Cell Physiology; Bacterial proteins; Biological activity; Biological products; Biomedical and Life Sciences; Biosynthesis; Biotechnology; Breast cancer; Discovery and exploration; Doxorubicin; Gene clusters; Gene sequencing; Genomes; Growth conditions; Life Sciences; Metabolites; Microbial Genetics and Genomics; Microbiology; Natural products; Physiological aspects; Regulatory proteins; Streptomyces; Tumor cell lines
• ISSN: 0175-7598; 1432-0614
• DOI: 10.1007/s00253-021-11344-5

Genome sequencing has revealed that each Streptomyces contains a wide range of biosynthetic gene clusters (BGCs) and has the capability to produce more novel natural products than what is expected. However, most gene clusters for secondary metabolite biosynthesis are cryptic under normal growth conditions. In Streptomyces tsukubaensis , combining overexpression of the putative SARPs ( Streptomyces antibiotic regulatory proteins) and bioactivity-guided screening, the silent gene cluster ( tsu ) was successfully activated and a novel bioactive anthracycline tsukubarubicin was further isolated and identified. Biological activity assays demonstrated that tsukubarubicin possessed much better antitumor bioactivities against various human cancer cell lines (especially the breast cancer cell lines) than clinically used doxorubicin. Moreover, the previously unreported gene cluster ( tsu ) for biosynthesis of tsukubarubicin was first characterized and detailed annotations of this gene cluster were also conducted. Our strategy presented in this work is broadly applicable in other Streptomyces and will assist in enriching the natural products for potential drug leads. Key points • Generally scalable strategy to activate silent gene clusters by manipulating SARPs . • The novel anthracycline tsukubarubicin with potent antitumor bioactivities . • Identification and annotation of the previously uncharacterized tsu gene cluster .