Merging the frontiers: synthetic biology for advanced bacteriophage design

doi:10.12211/2096-8280.2022-070

Abstract

Abstract:

Bacteriophages (phages), natural viruses known for infecting and killing bacteria, are the most diverse and abundant organisms on Earth. Within the past 100 years of research on phages, breakthroughs in genetics, molecular biology, and synthetic biology have been successfully achieved. The fascinating scientific history of phage therapy has been repeatedly reported, as drug-resistant bacteria are becoming increasingly prevalent. Although phages outnumber other species combined in nature (10³¹ in total), only a small fraction of them have been successfully exploited for fighting infections caused by drug-resistant bacteria. Therefore, there is an urgent need for implementing the motto of synthetic biology, "build to learn, build to use", and also using methods such as high-throughput sequencing and precise genome editing to create enhanced variants with unique features, improving efficacy and programmability for phage therapy. In the review, we discuss recent technological advances in phage genome engineering approaches and the potential applications of synthetic biology to engineer phages, such as modifying the host range of phages for practical needs, mining the extensive resources of phages in nature with the help of macro genomes, combining multi-omics technologies to reveal molecular mechanisms underlying phage-host interactions, regulating intestinal phages to maintain intestinal homeostasis for human health, and using big data and artificial intelligence to guide rational phage design. Synthetic biology is driving a paradigm shift in traditional experimental research by combining "Design-Build-Test-Learn (DBTL) cycles" to rational design for phages, making synthetically designed phages promising for both top-down system optimization and bottom-up life-form reconstruction.

Key words: phage, synthetic biology, engineered phage, reprogramming genome, rational design, phage therapy

CLC Number:

Q816

Qingli CHEN, Yigang TONG. Merging the frontiers: synthetic biology for advanced bacteriophage design[J]. Synthetic Biology Journal, 2023, 4(2): 283-300.

Figures/Tables 2

Fig. 1

Table 1

Applications of engineered phages through genetic modifications

策略	菌株	具体方法	年份	出处
随机诱变	T4噬菌体	紫外线诱变获取突变体	1966	[49]
随机诱变	T3、T7、肠道沙门氏菌噬菌体	改善噬菌体的热稳定性	2020	[51]
经典同源重组	T2噬菌体	改造尾丝蛋白结构	2009	[98].
	T4噬菌体	改变或扩大宿主T4样噬菌体宿主范围	2017	[99]
	T7噬菌体	T7噬菌体基因组的单碱基替换和全基因替换	2020	[55]
	T7噬菌体	获得新的RBP结构	2021	[100]
BRED	分歧杆菌噬菌体Giles	非必需基因缺失、读码框内缺失、点突变、无义突变、外源基因精确插入	2008	[58]
	肠杆菌科噬菌体P1	去除IS元件	2012	[60]
	沙门氏菌噬菌体	实现溶原和裂解性质转换	2014	[61]
	克雷伯氏菌噬菌体	建立了克雷伯氏菌噬菌体基因组的重组系统	2017	[62]
	分枝杆菌噬菌体BPs、ZoeJ	将治疗性温和噬菌体转化为烈性噬菌体	2019	[24]
CRISPR-Cas	链球菌噬菌体2972	Ⅱ-A型CRISPR-Cas实现特定点突变和大片段删除	2014	[64]
	T7噬菌体	Ⅰ-E型CRISPR-Cas系统编辑T7基因组	2014	[65]
	乳酸乳球菌烈性噬菌体P2	点突变，基因缺失和替换	2017	[66]
	克雷伯氏菌噬菌体	点突变，基因缺失和替换	2018	[68]
	金黄色葡萄球菌噬菌体	Ⅲ-A型CRISPR-Cas系统CRISPR-Cas10	2019	[69]
	T4噬菌体	Ⅴ型CRISPR-Cas12a系统构建包含缺失和插入的重组T4	2021	[70]
	T5噬菌体	Ⅱ-A型CRISPR-Cas9系统效果不稳定，提出基于Retron的重组方案	2021	[75]
	需钠弧菌噬菌体TT4	使用CRISPR-Cas9基因的缺失和替换	2022	[71]
	大肠杆菌噬菌体	CRISPR-Cas13a	2022	[72]
	ФKZ、OMKO1和PaMx41噬菌体	CRISPR-Cas13a+正向选择基因acrVIA1	2022	[73]
Genome Reboot	大肠杆菌、克雷伯氏菌噬菌体	YAC	2015	[78]
	PICIs	YAC	2020	[80]
	铜绿假单胞菌噬菌体	YAC	2021	[79]
	大肠杆菌噬菌体	电转重启	2019	[84]
	沙门氏菌噬菌体	电转重启	2022	[85]
	MS2噬菌体	无细胞体系	1996	[89]
	T7噬菌体	无细胞体系	2012	[91]
	T4噬菌体	无细胞体系	2018	[86]
	耶尔森氏菌噬菌体	无细胞体系	2022	[88]
	克雷伯氏菌噬菌体	无细胞体系	2022	[88]
	抗酸性分枝杆菌噬菌体	无细胞体系	2022	[92]
	李斯特氏菌、芽孢杆菌、葡萄球菌噬菌体	L-forms	2018	[96]

Table 1

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