达托霉素生物合成过程的调控机制研究进展

doi:10.12211/2096-8280.2020-020

合成生物学 ›› 2020, Vol. 1 ›› Issue (6): 722-731.DOI: 10.12211/2096-8280.2020-020

达托霉素生物合成过程的调控机制研究进展

方教乐^1,², 吕中原^1,², 孙晨番^1,², 刘一帆^1,², 徐炜锋^1,², 毛旭明^1,², 李永泉^1,²

^1.浙江大学药物生物技术研究所，浙江杭州 310058
^2.浙江省微生物生化与代谢工程重点实验室，浙江杭州 310058

收稿日期:2020-03-10 修回日期:2020-11-05 出版日期:2020-12-31 发布日期:2021-01-15
通讯作者: 毛旭明,李永泉
作者简介:方教乐（1991—），男，博士研究生，研究方向为微生物次级代谢产物调控，链霉菌隐性基因簇激活，表观遗传学研究。E-mail：fjl20@live.cn|毛旭明（1978—），男，博士，教授，研究方向为基于合成生物学的微生物药物开发、微生物药物生物合成的调控机制研究、基于多组学的新活性和新结构微生物天然产物挖掘、微生物天然产物生物合成的酶学机制和化学机制研究。E-mail：xmmao@zju.edu.cn|李永泉（1962—），男，博士，求是特聘教授，研究方向为微生物合成生物学、微生物次级代谢调控和微生物制药。E-mail：lyq@zju.edu.cn
基金资助:
国家新药创制重大专项(2018ZX09711001-006-013);国家自然科学基金(3173002)

An overview on regulatory mechanism of daptomycin biosynthesis

Jiaole FANG^1,², Zhongyuan LYU^1,², Chenfan SUN^1,², Yifan LIU^1,², Weifeng XU^1,², Xuming MAO^1,², Yongquan LI^1,²

^1.Institute of Pharmaceutical Biotechnology，Zhejiang University，Hangzhou 310058，Zhejiang，China
^2.Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering，Hangzhou 310058，Zhejiang，China

Received:2020-03-10 Revised:2020-11-05 Online:2020-12-31 Published:2021-01-15
Contact: Xuming MAO,Yongquan LI

摘要/Abstract

摘要：

微生物是天然产物类药物的重要来源之一，其中许多链霉菌来源的抗生素类药物一直活跃在对付细菌感染的前沿阵地。然而随着“超级细菌”的陆续发现，以及新药研发速度的滞缓，人类尚缺乏“超级细菌”的最终治疗手段。达托霉素是由玫瑰孢链霉菌（Streptomyces roseosporus）经发酵产生的一种新型环脂肽类抗生素，由于其独特的结构及特殊的药物机制，被视为多重耐药革兰阳性细菌引起的重症感染的最后一道防线。然而在工业发酵过程中，达托霉素的生物合成水平很低，有极高的提升潜力。本文总结了近年来国内外相关达托霉素合成的调控机制研究，包括调控蛋白的挖掘、途径特异性调控机制、级联调控途径、脂酰前体合成途径、GBL信号途径与磷酸双组分系统及其协同调控机制等，揭示了次级代谢调控网络的复杂性，并阐述了通过调控通路重构实现达托霉素优质高产的策略。

关键词: 达托霉素, 生物合成, 调控网络, A因子级联调控途径, 磷酸双组分系统

Abstract:

Daptomycin is a new cyclic lipopeptide antibiotic, produced by Streptomyces roseosporus, with strong resistance to Gram-positive bacteria. Due to its special manner to block the biosynthesis of peptidoglycan, it is difficult for bacteria to develop resistance to daptomycin. Therefore, daptomycin is also known as the ‘last line of defense’ after vancomycin.After approval of daptomycin for injection (brand name cubicin) used to treat infections caused by some sensitive Gram-positive strains, domestic daptomycin products still mainly rely on imports to keep up with demand. In response to this urgent need, there have been many studies on the structure, physicochemical properties, functional mechanisms and synthesis of daptomycin. The biosynthetic pathway of daptomycin has no typical pathway-specific regulators, suggesting that its synthetic regulation may have a unique mechanism. Based on analysis of daptomycin biosynthetic gene cluster, this article mainly summarizes researches on the regulatory mechanism during daptomycin biosynthesis. Screening and identifying regulatory pathways for daptomycin biosynthesis is of great significance for enriching the secondary metabolic regulation of streptomyces, and will also provide important candidate targets for improving daptomycin production. This review aims to give directions for the targeted transformation to obtain high-yield strains more efficiently, and to provide a theoretical reference for the improved biosynthesis of daptomycin. The regulation of microbial secondary metabolism can be divided into three levels, namely global regulation, pleiotropic regulation and pathway-specific regulation. Through analyzing and constructing a regulatory network for the synthesis of secondary metabolites, we can see the key targets of genetic transformation and provide an entry point for high-yield strategies for secondary metabolism, thereby helping us to more effectively carry out targeted high-yield transformation of bacteria and increase the yield of metabolites. With the identifications of gene functions in the daptomycin synthesis gene cluster and the clarification of the daptomycin biosynthesis regulatory network, more genetically targeted transformation and breeding optimization methods have emerged. At the same time, with the development and optimization of the fermentation process, the goal of greatly increasing production of daptomycin biosynthesis in China can be achieved.

Key words: daptomycin, biosynthesis, regulatory network, A-factor, PhoR-PhoP

中图分类号:

Q939.97

方教乐, 吕中原, 孙晨番, 刘一帆, 徐炜锋, 毛旭明, 李永泉. 达托霉素生物合成过程的调控机制研究进展[J]. 合成生物学, 2020, 1(6): 722-731.

Jiaole FANG, Zhongyuan LYU, Chenfan SUN, Yifan LIU, Weifeng XU, Xuming MAO, Yongquan LI. An overview on regulatory mechanism of daptomycin biosynthesis[J]. Synthetic Biology Journal, 2020, 1(6): 722-731.

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达托霉素生物合成过程的调控机制研究进展

An overview on regulatory mechanism of daptomycin biosynthesis

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