Stepwise increase of fidaxomicin in an engineered heterologous host Streptomyces albus through multi-level metabolic engineering  

作　　者：Huang Xie Yi-Ting Su Qing-Ting Bu Yue-Ping Li Qing-Wei Zhao Yi-Ling Du Yong-Quan Li 

机构地区：[1]First Affiliated Hospital and Institute of Pharmaceutical Biotechnology,Zhejiang University School of Medicine,Hangzhou 310058,China [2]Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering,Hangzhou 310058,China

出　　处：《Synthetic and Systems Biotechnology》2024年第4期766-774,共9页合成和系统生物技术(英文)

基　　金：supported by the National Key R&D Program of China(grant number 2019YFA09005400);the Zhejiang Provincial Natural Science Foundation of China(grant number LQ21C010002).

摘　　要：The anti-Clostridium difficile infection(CDI)drug fidaxomicin is a natural polyketide metabolite mainly produced by Micromonosporaceae,such as Actinoplanes deccanensis,Dactylosporangium aurantiacum,and Micromonospora echinospora.In the present study,we employed a stepwise strategy by combining heterologous expression,chassis construction,promoter engineering,activator and transporters overexpression,and optimization of fermentation media for high-level production of fidaxomicin.The maximum yield of 384 mg/L fidaxomicin was achieved with engineered Streptomyces albus D7-VHb in 5 L-tank bioreactor,and it was approximately 15-fold higher than the native strain Actinoplanes deccanensis YP-1 with higher strain stability and growth rate.This study developed an enhanced chassis strain,and for the first time,achieved the heterologous synthesis of fidaxomicin through a combinatorial metabolic engineering strategy.

关 键 词：Fidaxomicin Heterologous expression Streptomyces albus Genome-reduced chassis Metabolic engineering 

分 类 号：Q78[生物学—分子生物学]