微生物药物的合成生物学研究进展

doi:10.12211/2096-8280.2020-036

合成生物学 ›› 2020, Vol. 1 ›› Issue (1): 92-102.DOI: 10.12211/2096-8280.2020-036

微生物药物的合成生物学研究进展

饶聪¹, 云轩¹, 虞沂¹, 邓子新^1,²

^1.武汉大学药学院，组合生物合成与新药发现教育部重点实验室，湖北武汉 430071
^2.上海交通大学生命科学技术学院，微生物代谢国家重点实验室，上海 200240

收稿日期:2020-03-26 修回日期:2020-04-19 出版日期:2020-02-25 发布日期:2020-07-07
通讯作者: 虞沂,邓子新
作者简介:饶聪（1996-），男，硕士研究生。|虞沂（1978—），男，教授，博士生导师，研究方向为天然产物化学生物学。E-mail： yu_yi@whu.edu.cn|邓子新（1957—），男，中国科学院院士，第三世界科学院（TWAS）院士，美国微生物科学院院士，2020年当选全球工业微生物学会（GIM）首届主席，主要从事放线菌遗传学及抗生素生物合成的化学生物学、合成生物学研究。E-mail：zxdeng@sjtu.edu.cn
基金资助:
国家重点研发计划(2018YFA0900400);国家自然科学基金(31870035)

Recent progress of synthetic biology applications in microbial pharmaceuticals research

Cong RAO¹, Xuan YUN¹, Yi YU¹, Zixin DENG^1,²

^1.Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Ministry of Education), School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, Hubei, China
^2.State Key Laboratory of Microbial Metabolism, School of Life Science & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China

Received:2020-03-26 Revised:2020-04-19 Online:2020-02-25 Published:2020-07-07
Contact: Yi YU,Zixin DENG

摘要/Abstract

摘要：

微生物天然产物一直都是新型生物药物创新的主要源泉，是目前开发临床抗菌、抗肿瘤、免疫抑制剂等药物的重要资源。随着临床耐药菌的日益增多，新型病原菌和病毒的不断出现，以及新骨架天然产物挖掘难度的增加，新型微生物药物的开发正面临着巨大挑战。作为21世纪生命医学领域催动原创突破和学科交叉融合的前沿学科，合成生物学的崛起为解决药物研发困境提供了新的思路和方法，它可以突破天然药物发现的瓶颈，设计新的生物合成途径，产生更多天然药物及类似物。本文综述了近五年来合成生物学在微生物药物研究领域的技术革新，及其在氨基糖苷类抗生素、核苷类抗生素、核糖体肽、萜类以及聚酮类化合物等5大类微生物天然药物的发掘、生物合成以及新结构创制等方面的应用。

关键词: 天然产物, 合成生物学, 微生物药物, 生物合成, 暗物质

Abstract:

Microbial natural products are a major source in the innovation of novel pharmaceuticals, including anti-bacterial, anti-tumor, and immunosuppressive agents for clinical use. Currently, the development of microbial drugs is facing significant challenges due to the growing prevalence of multidrug-resistant bacteria, the continuous emergence of new pathogens and viruses, and the increasing difficulties in the discovery of natural products with new scaffolds. Synthetic biology is an emerging interdisciplinary research area leading to great breakthrough in the field of biomedical sciences in the 21st century, which provides new methods and ideas for drug discovery and development. The application of synthetic biology could unlock the potential of natural product mining, design new biosynthetic routes, and generate much more “unnatural” natural products and structural analogs. This review summarizes the technical innovations of synthetic biology in the field of microbial pharmaceuticals, and its applications in the mining, biosynthesis, and new scaffold generation of aminoglycoside antibiotics, nucleotide antibiotics, ribosomally synthesized and posttranslationally modified peptides, terpenoids, and polyketides in the last five years.

Key words: natural products, synthetic biology, microbial pharmaceuticals, biosynthesis, dark matter

中图分类号:

饶聪, 云轩, 虞沂, 邓子新. 微生物药物的合成生物学研究进展[J]. 合成生物学, 2020, 1(1): 92-102.

Cong RAO, Xuan YUN, Yi YU, Zixin DENG. Recent progress of synthetic biology applications in microbial pharmaceuticals research[J]. Synthetic Biology Journal, 2020, 1(1): 92-102.

图/表 4

图1 Valienamine天然多步合成途径及改造后的简化合成途径

Fig. 1 The natural multistep biosynthetic pathway of valienamine, and the simplified biosynthetic pathway after modification

图2 嘌呤核苷类抗生素的靶向基因组挖掘

Fig. 2 Targeted genome mining of purine nucleoside antibiotics

图3 喹啉酸及其类似物喂养工程菌SL3052产生siomycin及其类似物

Fig. 3 The engineered strain SL3052 fed with quinolinic acid and its analogues, leading to the production of siomycin and its analogues

图4 酿酒酵母中萜类化合物合成通路

Fig. 4 The synthesis pathway of terpenoids in Saccharomyces cerevisiae

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微生物药物的合成生物学研究进展

Recent progress of synthetic biology applications in microbial pharmaceuticals research

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