细菌群体感应元件构建和工程应用

doi:10.12211/2096-8280.2020-066

合成生物学 ›› 2021, Vol. 2 ›› Issue (2): 234-246.DOI: 10.12211/2096-8280.2020-066

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^,³^,⁴

^1.上海科技大学物质科学与技术学院，上海 201210
^2.上海科技大学生命科学与技术学院，上海 201210
^3.中国科学院深圳先进技术研究院，深圳合成生物学创新研究院，中国科学院定量工程生物学重点实验室，广东　深圳 518055
^4.中国科学院深圳先进技术研究院，深圳合成生物学创新研究院，材料合成生物学中心，广东　深圳 518055

收稿日期:2020-06-05 修回日期:2021-02-19 出版日期:2021-04-30 发布日期:2021-04-30
通讯作者: 钟超
作者简介:周爱林（1999—），女，主要研究方向为合成生物学的研究。E-mail：zhoual@shanghaitech.edu.cn
钟超（1979—）,男，博士，研究员。主要研究方向为利用合成生物学技术发展新材料和生物纳米技术，包括基于蛋白的水下黏合胶水和细菌生物被膜活体功能材料。E-mail：chao.zhong@siat.ac.cn
基金资助:
国家自然科学基金(U1932204);国家重点研发计划(2018YFA0902804);上海市科学技术委员会项目(17JC1403900)

Construction and engineering application of bacterial quorum sensing elements

ZHOU Ailin¹^,², LIU Yi¹, BA Fang¹, ZHONG Chao¹^,³^,⁴

^1.Materials and Physical Biology Division，School of Physical Science and Technology，ShanghaiTech University，Shanghai 201210，China
^2.School of Life Science and Technology，ShanghaiTech University，Shanghai 201210，China
^3.CAS Key Laboratory of Quantitative Engineering Biology，Shenzhen Institute of Synthetic Biology，Shenzhen Institutes of Advanced Technology，Chinese Academy of Sciences，Shenzhen 518055，Guangdong，China
^4.Center for Materials Synthetic Biology，Shenzhen Institute of Synthetic Biology，Shenzhen Institutes of Advanced Technology，Chinese Academy of Sciences，Shenzhen 518055，Guangdong，China

Received:2020-06-05 Revised:2021-02-19 Online:2021-04-30 Published:2021-04-30
Contact: ZHONG Chao

摘要/Abstract

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

中图分类号:

Q819

周爱林, 刘奕, 巴方, 钟超. 细菌群体感应元件构建和工程应用[J]. 合成生物学, 2021, 2(2): 234-246.

ZHOU Ailin, LIU Yi, BA Fang, ZHONG Chao. Construction and engineering application of bacterial quorum sensing elements[J]. Synthetic Biology Journal, 2021, 2(2): 234-246.

图/表 6

图1 群体感应的提出及研究进程[1-4,15,19-23]

Fig. 1 Research progress of quorum sensing[1-4,15,19-23]

图2 群体感应系统的开发与优化

Fig. 2 Development and optimization of quorum sensing systems

表1 化学诱导与群体感应在代谢调控中应用的对比[23-24,26,39-40]

Tab. 1 Comparison between chemical inducers and quorum sensing on their application in metabolic regulation[23-24,26,39-40]

较好

可以人为通过加入化学诱导剂，较为精确地控制基因表达的时间

较好

群体感应的基因表达开启与否本来由元件内源参数决定，除了在使用前改造元件、调整内源参数，还可以将群体感应中自体诱导物的启动子替换为外源分子调控的诱导型启动子，通过外加特定的诱导物实现对群体感应行为的控制^[26]

动态性

较差

需要实时检测细胞生长状况，并在合适的时机添加诱导剂

较好

群体数量实时决定群体行为

可逆性

较差

一经添加便会一直存在于介质中，只能起到单次控制的效果^[40]

较差，但可以优化

Miano等^[23]通过构建基于诱导物的酶促反应链，搭建调控严谨且能多次开关的群体感应系统（iQS）

经济性

较差

现常用的化学诱导剂如IPTG等成本较高^[39]，不适合大规模工业生产使用^[24]

较好

只在最初基因回路构建上存在一次性成本

图3 三种典型的基因回路用于调节细胞振荡行为

Fig. 3 Three typical gene circuits used for regulating intracellular oscillation behaviors

图4 三种典型思路用于构建多细胞振荡体系[30, 56-57][(a),(b),(c)分别对应三种振荡回路与群体感应结合的思路；（d）利用群体感应形成规律图案[基于思路二构建的系统，通过群体感应，自体诱导物AHL的浓度周期性到达阈值，而菌落边缘的细菌有更强的基因表达能力（表达荧光蛋白），两者构成AND逻辑门，使菌落呈现出规律的图案]；（e）实现更大范围群体周期性行为的同步；（f）利用群体感应实现的震荡系统治疗癌症]

Fig. 4 Three strategies for construcling multicellular oscillation systems[30, 56-57][(a), (b) and (c) refers to each of the three strategies for combining oscillation circuit with quorum sensing.（d）Forming regular pattern using QS.By using method B, autoinducer concentration periodically reaches the threshold. Since only bacteria at the edge of the colony have higher gene expression (like the expression of fluorescent protein),an AND logic gate is constructed to make the colony show rhythmic pattern.（e）Realization of the collective oscillation in a bigger range.（f）Employment of QS oscillation system in cancer treatment]

图5 微生物复杂种间关系的构建案例[63,68-70]

Fig. 5 Cases of the construction of complex bacterial interspecific relationship[63,68-70]

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细菌群体感应元件构建和工程应用

Construction and engineering application of bacterial quorum sensing elements

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