6-methy salicylic acid synthetase transformed by genetic engineering and combinatorial biosynthesis of spirocyclic acetoacetic acid lactone antiboitic

Abstract

The invention discloses a novel method for synthesizing spirocyclic acetoacetic acid lactone antibiotic with higher activity by using combinatorial biosynthesis based on a genetic engineering method. The method is characterized by carrying out specific locus mutation on the keto-reduction (KR) conservation activity locus of a 6-methy salicylic acid (6-MSA) synthetase and genetically transforming the producing strain Streptomyces antibioticus DSM40725 of chlorothrichin (CHL) and fermenting to generate new chlorothrichin analogues 7 and 8 with improved biological activity. The favorable biological activity of the new chlorothrichin analogues 7 and 8 has values to be developed into medicaments.

Description

technical field The invention belongs to the field of biotechnological engineering, and specifically relates to the function of genetic engineering modification of 6-MSA synthetase, the fermentation, separation, structure identification and activity determination of new compound biosynthesis in recombinant bacterial strain combination. Background technique Natural compounds are a major source of drug discovery and development, such as penicillin and erythromycin for anti-infection, bleomycin and etomycin for anti-tumor, avermectin for anti-parasite and immunosuppressant cyclosporine etc., have been the main drugs for human treatment of diseases in the past few decades. Therefore, the research and development of new drugs based on natural compounds has always been a key area of ​​concern in the chemical and medical circles. Among them, the natural products derived from microorganisms account for an important part. There are thousands of microbial natural products reported so...

AI Technical Summary

Problems solved by technology

However, its complex chemical structure has brought great challenges to chemical synthesis and structure derivation. Due to the excessive chiral centers and concentrated functional groups, chemical synthesis has very limited prospects for the production of CHL and its analogues. An important supplement, the development of combinatorial biosynthesis technology provides a new method for the acquisition of complex natural products and their analogs

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