海洋放线菌沉默次级代谢物生物合成基因簇激活策略的现状与展望

Current status and future perspectives of strategies for activating silent secondary metabolite biosynthetic gene clusters in marine actinomycetes

摘要:

在海洋高盐、高渗、寡营养的特殊环境之中，海洋放线菌进化出了独特的生存策略，其部分次级代谢产物凭借新颖的结构和良好的生物活性，在医药开发领域具有重要的研究与应用价值。在实验室常规培养条件下，海洋放线菌仅有20%的生物合成基因簇(biosynthetic gene clusters, BGCs) 得以表达，大量处于沉默状态的BGCs亟待开发。本文系统梳理了海洋放线菌沉默BGCs的沉默机制与激活策略，全面总结近几年物理激活、化学激活、生物工程技术领域的研究成果，深入剖析各类激活方法的优势与局限性，并针对沉默BGCs的激活提出了多技术联用策略。多技术联用策略可从多方面模拟微生物原始生存环境或针对基因簇构造特定表达环境，多层面促进、诱导沉默BGCs表达，进而获得新颖次级代谢产物，为挖掘海洋放线菌代谢潜力、推动新型天然产物发现提供理论参考与技术路径。

Abstract:

In the special marine environment characterized by high salinity, high osmotic pressure, and oligotrophy, marine actinomycetes have evolved unique survival strategies. Some of their secondary metabolites, with novel structures and potent biological activities, hold significant research and application value in pharmaceutical development. Under conventional laboratory culture conditions, only 20% of the biosynthetic gene clusters (BGCs) in marine actinomycetes are expressed, and a large number of silent BGCs urgently need to be explored. This paper systematically reviews the silencing mechanisms and activation strategies of silent BGCs in marine actinomycetes, comprehensively summarizes recent research advances in physical activation, chemical activation, and bioengineering technologies, and deeply analyzes the advantages and limitations of various activation methods. The silencing of BGCs often resulted from the combined effects of multiple factors. Therefore, this paper proposes a multi-technology combination strategy for activating silent BGCs. This strategy simulates the original survival environment of microorganisms from multiple aspects or constructs specific expression environments for gene clusters to promote and induce the expression of silent BGCs at multiple levels, thereby obtaining novel secondary metabolites. This strategy provides theoretical references and technical pathways for exploring the metabolic potential of marine actinomycetes and promoting the discovery of new natural products.