Abstract:

Bacteriophage (phage) are viruses that specifically infect bacterial and archaea. Phage is the most diverse and abundant biological entity on the planet. For more than a century, phage is one of the most important model organisms in the molecular biological research. Many important discoveries upon phage research have enabled us to understand the mechanisms of genetic materials in biological activities, and many phage-derived enzymes are greatly useful in the molecular biological research. Phage has also been recognized as natural antimicrobial agents for treating the bacterial infections. In particular, nowadays, the concern related to the emergence of bacteria resistance to multiple antibiotics is increasing. However, the challenges in phage therapy, such as narrow host range and bacterial resistance, limited the application of phage therapy in treating the diseases of antibiotic-resistant bacterial infections. Novel strategies are needed to be developed to overcome the hurdles associated with phage therapy. Synthetic biology aims to design and reprogram new biological systems according to the known principles. Because of their relatively small genome size (5—735 kb), fast growth rate, ease of genetic manipulation, and simple structure, phages have become the most important biological system for synthetic biology research. In this review, we discuss the advances of synthetic biology facing the major challenges of natural phages in basic and application research. For example, synthetic biology has been applied to enhance the infection efficiency of phages, improve the phage biosafety, alter the phage host ranges, adjust the bacterial communities, and knock out the specific bacterial genes. We also present some examples to show the methods that were widely used for phage engineering to obtain phages with new functions. In addition, phage display and phage-assisted continuous evolution have also become powerful tools in synthetic biology. In short, the development of synthetic biology will inspire scientists to design modular phages as multifunctional biological agents for clearance of multi-drug resistant bacteria, detection of the pathogen, regulation of bacterial diversity, and drug delivery.

Key words: phage, synthetic biology, synthetic genome, phage display, diagnostics, phage therapy

摘要：

噬菌体是地球上多样性最高和最丰富的生物体，也是合成生物学研究中重要的模式生物。噬菌体基因组相对较小，结构简单，是研究基本生命过程最简单的生物系统。通过对噬菌体基因组进行编辑，乃至重新设计、合成噬菌体基因组，获得具有新的功能的噬菌体，是当前噬菌体合成生物学研究的重要内容。本文综述了当前合成生物学在解决天然噬菌体的基础研究和应用研究中的主要进展，如通过人工改造的噬菌体已成功用于提高噬菌体的侵染效率，调节噬菌体宿主范围，降低噬菌体毒性和免疫原性，提高给药后噬菌体存活周期，提高噬菌体对生物膜的降解等；此外，噬菌体展示、噬菌体辅助的持续进化和噬菌体介导的DNA转导等也成为合成生物学研究中强大的工具。总之，合成生物学的发展将为模块化设计噬菌体作为多功能生物制剂、控制多重耐药细菌、病原体检测、药物开发、菌群的调控、药物递送，甚至噬菌体纳米材料等铺平道路。

关键词: 噬菌体, 合成生物学, 人工合成基因组, 噬菌体展示, 诊断, 噬菌体治疗