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 ...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.展开更多
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).
文摘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.
