Heterologous expression of oxytetracycline biosynthetic gene cluster in Streptomyces venezuelae WVR2006 to improve production level and to alter fermentation process

• Published in: Applied microbiology and biotechnology Vol. 100; no. 24; pp. 10563 - 10572
• Main Authors: Yin, Shouliang, Li, Zilong, Wang, Xuefeng, Wang, Huizhuan, Jia, Xiaole, Ai, Guomin, Bai, Zishang, Shi, Mingxin, Yuan, Fang, Liu, Tiejun, Wang, Weishan, Yang, Keqian
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2016; Springer; Springer Nature B.V
• Subjects: Anti-Bacterial Agents - biosynthesis; Antibiotics; Applied Genetics and Molecular Biotechnology; Bacteria; Biomedical and Life Sciences; Biosynthesis; Biosynthetic Pathways - genetics; Biotechnology; Cloning, Molecular; Drug Resistance, Bacterial; E coli; Fermentation; Gene Expression; Genes; Genetic aspects; Genetic engineering; Life Sciences; Metabolic Engineering; Metabolism; Metabolites; Microbial Genetics and Genomics; Microbiology; Multigene Family; Observations; Oxytetracycline - biosynthesis; Plasmids; Regulation; Secondary metabolites; Streptomyces; Streptomyces - drug effects; Streptomyces - genetics; Streptomyces - growth & development; Streptomyces - metabolism; Streptomyces rimosus; Streptomyces venezuelae; Studies; Oxytetracycline; Fermentation process; Metabolic engineering; Biosynthetic gene cluster; Heterologous expression; Streptomyces venezuelae
• ISSN: 0175-7598; 1432-0614
• DOI: 10.1007/s00253-016-7873-1

Heterologous expression is an important strategy to activate biosynthetic gene clusters of secondary metabolites. Here, it is employed to activate and manipulate the oxytetracycline (OTC) gene cluster and to alter OTC fermentation process. To achieve these goals, a fast-growing heterologous host Streptomyces venezuelae WVR2006 was rationally selected among several potential hosts. It shows rapid and dispersed growth and intrinsic high resistance to OTC. By manipulating the expression of two cluster-situated regulators (CSR) OtcR and OtrR and precursor supply, the OTC production level was significantly increased in this heterologous host from 75 to 431 mg/l only in 48 h, a level comparable to the native producer Streptomyces rimosus M4018 in 8 days. This work shows that S. venezuelae WVR2006 is a promising chassis for the production of secondary metabolites, and the engineered heterologous OTC producer has the potential to completely alter the fermentation process of OTC production.