Dalbavancin is a novel glycopeptide antibiotic with activity against a broad range of Gram-positive bacteria,including methicillin-resistant Staphylococcus aureus(MRSA).A40926B0 is the direct precursor of dalbavancin,...Dalbavancin is a novel glycopeptide antibiotic with activity against a broad range of Gram-positive bacteria,including methicillin-resistant Staphylococcus aureus(MRSA).A40926B0 is the direct precursor of dalbavancin,but the regulatory mechanisms underlying its biosynthesis are not well understood.Additionally,the presence of seven homologs leads to significant metabolic burden,affecting both production and purity of A40926B0.To further reveal the transcriptional regulatory mechanism of A40926B0 biosynthesis in N.gerenzanensis L70,this study employed multiple strategies to explore the regulatory network of its biosynthesis from both intracluster and extracluster aspects.WblA regulates gene expression within and outside the biosynthetic gene cluster(BGC),impacting multiple biosynthetic pathways,and Dbv3,a key regulator in the A40926B0 cluster,positively in-fluences biosynthesis.Using a bottom-up(DNA to protein)regulator mining strategy with the key intra-cluster regulator Dbv3,it was determined that GlnR is also involved in the regulation of secondary metabolism,while BkdR regulates precursor supply.By constructing the combination of GlnR,BkdR and Dbv3 together with the WblA deletion,the regulatory network of A40926B0 was reconstructed,resulting in a 92%improvement in purity of A40926B0.The objective of this study is to elucidate the regulatory mechanisms governing A40926B0 biosynthesis by constructing a comprehensive,multidimensional model of its regulatory network.The findings of this study serve to enhance our comprehension of A40926B0 biosynthesis and furnish insights into broader strategies for enhancing the production of other natural products and secondary metabolites in industrial microbiology.展开更多
双组份信号转导系统是放线菌中重要的全局调控系统之一,参与细胞形态分化、氮磷代谢、次级代谢产物合成和其他生理代谢过程。本文采用生物信息学方法系统分析了Nonomuraea sp.中双组份信号转导系统(two-component signal transduction s...双组份信号转导系统是放线菌中重要的全局调控系统之一,参与细胞形态分化、氮磷代谢、次级代谢产物合成和其他生理代谢过程。本文采用生物信息学方法系统分析了Nonomuraea sp.中双组份信号转导系统(two-component signal transduction system,TCS)的分布、系统分类、结构与功能,初步构建了部分TCS调控网络,旨在揭示Nonomuraea sp.中次级代谢产物合成与TCS之间的关系,为提高糖肽抗生素A40926效价和发现新的潜在生物活性物质奠定基础。展开更多
基金supported by the National Natural Science Foundation of China(grant number 32170057).
文摘Dalbavancin is a novel glycopeptide antibiotic with activity against a broad range of Gram-positive bacteria,including methicillin-resistant Staphylococcus aureus(MRSA).A40926B0 is the direct precursor of dalbavancin,but the regulatory mechanisms underlying its biosynthesis are not well understood.Additionally,the presence of seven homologs leads to significant metabolic burden,affecting both production and purity of A40926B0.To further reveal the transcriptional regulatory mechanism of A40926B0 biosynthesis in N.gerenzanensis L70,this study employed multiple strategies to explore the regulatory network of its biosynthesis from both intracluster and extracluster aspects.WblA regulates gene expression within and outside the biosynthetic gene cluster(BGC),impacting multiple biosynthetic pathways,and Dbv3,a key regulator in the A40926B0 cluster,positively in-fluences biosynthesis.Using a bottom-up(DNA to protein)regulator mining strategy with the key intra-cluster regulator Dbv3,it was determined that GlnR is also involved in the regulation of secondary metabolism,while BkdR regulates precursor supply.By constructing the combination of GlnR,BkdR and Dbv3 together with the WblA deletion,the regulatory network of A40926B0 was reconstructed,resulting in a 92%improvement in purity of A40926B0.The objective of this study is to elucidate the regulatory mechanisms governing A40926B0 biosynthesis by constructing a comprehensive,multidimensional model of its regulatory network.The findings of this study serve to enhance our comprehension of A40926B0 biosynthesis and furnish insights into broader strategies for enhancing the production of other natural products and secondary metabolites in industrial microbiology.
