细菌群体感应元件构建和工程应用

周爱林1,2, 刘奕1, 巴方1, 钟超1

摘要：

群体感应现象指的是微生物通过独特的交流方式使不同菌个体间的行为同步，从而展现群体性行为。当前在微生物群体感应系统方面的研究，除了促进或抑制天然群体感应方面的基础研究外，研究人员逐渐开始将群体感应系统引入到合成生物学的工程应用研究，并且将其广泛运用在医学、工业、环境等应用领域。本文主要总结了细菌群体感应元件在构建过程中的常用策略与方法，并探讨了基于群体感应基因元件改造的工程菌在动态代谢调节、周期性振荡呈现、异种菌种间关系的构建等方面的应用。 群体感应元件的研究主要包括新群体感应元件的开发和针对已有群体感应元件的优化。通过模拟、优化群体感应元件并将其模块化，研究人员构建了丰富的群体感应基因元件库，使群体感应能被灵活应用于不同场景。另外，通过在细菌中引入群体感应基因回路，可以将单个细菌内部的各类反馈回路较好地拓展到整个细菌群体中，而这种多细胞体系的构建，使得更多复杂的功能得以实现，如通过群体感应实现动态代谢调节从而提高发酵效率，或实现群体周期性振荡以释放肿瘤杀伤药物等。此外，环境中异种微生物的关系也可以通过外源引入群体感应来进行调控，这为微生物的共培养提供了新工具，更为复杂的合成生物学系统的建立提供了新思路。随着机器学习等计算机领域的发展，未来可以更多借助计算机来设计复杂群体感应回路，并对外源群体感应引入后的效果做出更精准的预测。

关键词: 群体感应, 合成生物学, 基因元件, 微生物, 代谢调控

Abstract:

Quorum sensing refers to the specific communication among bacteria which could synchronize individual behaviors to collective benefits. This mechanism relies on the production, detection, and response to extracellular signaling molecules called autoinducers. Based on the understanding of scientific fundamentals underlying the activation and inhibition of natural quorum sensing systems, researchers attempt to introduce quorum sensing into engineering applications as modules or gene parts through synthetic biology, and employ it in fields such as medicine, industry and environment. In this review, strategies and methods used in the construction of quorum sensing system are briefly discussed, and the promising applications of engineered bacteria with quorum sensing for dynamic metabolic reflux, oscillation, and microbial consortia are also highlighted. The construction of quorum sensing elements requires the grasp of its essence, which involves the development of new elements and the optimization of existing ones. By simulating natural quorum sensing systems, and optimizing and modularizing quorum sensing elements, researchers construct libraries for quorum sensing elements, making them possible to employ quorum sensing under different circumstances. Moreover, by introducing quorum sensing, various feedback loops initially possessed by a single bacterium could be extended to the whole population. With the construction of such multicellular quorum sensing systems, more complex functions could be initiated, such as dynamic regulation of metabolic flux for boosting fermentation efficiency, robust production of drugs by collective oscillation and so on. In addition, microbial consortia containing could be manipulated by introducing exogenous quorum sensing systems, providing new tools for microbial co-culture and new ideas for the construction of biological systems with higher complexity. In the future, machine learning will be applied for designing complex quorum sensing circuits and accurately predicting the behavior of exogenous quorum sensing systems in certain microbial population.

Key words: quorum sensing, synthetic biology, genetic elements, bacteria, metabolic flux regulation