抗菌肽的生物合成及医学应用

doi:10.12211/2096-8280.2022-001

摘要/Abstract

摘要：

因具有广谱抗菌性和低耐药性，天然抗菌肽成为潜在的抗生素替代品之一，并有望解决长期困扰人类的耐药菌感染问题。除了抗细菌和真菌等微生物病原体，抗菌肽还具备抗癌、抗病毒、抗寄生虫和调节免疫等诸多作用，具有巨大的医学应用前景。本文介绍了抗菌肽的分布和抗性原理，重点归纳抗菌肽的生物合成方法，对比分析依托微生物表达系统的多种抗菌肽生物合成体系的利弊，并介绍合成生物学等新型交叉学科及手段在抗菌肽的设计策略，并总结了抗菌肽在消炎类药品、抗病毒药物、抗寄生虫药品、抗癌药物、医学组织工程、药物递送系统、皮肤护理与医疗美容七大医学领域的应用。同时，本文针对抗菌肽生物合成含量少、分离提取困难、成本高、稳定性差、生物安全不足等潜在问题，提出了潜在的解决方案，包括利用计算机预测与定向基因编辑技术创建新型抗菌肽，以提升其抗菌性能，降低生物毒性；完善抗菌肽生物合成的工业化体系，开发快速回收高纯度抗菌肽的策略；将抗菌肽与现有抗生素联合用药，预防传统抗生素的细菌耐药性；与新型生物材料结合，降低抗菌肽对体内其他组织器官的损伤等。

关键词: 抗菌肽, 防御素, 合成生物学, 生物工程, 组织工程

Abstract:

Due to their broad-spectrum antibacterial activity and low incidence of drug resistance, natural antimicrobial peptides have become a potential alternative to antibiotics. In addition to being able to control pathogenic bacteria and fungi, antimicrobial peptides also have many other biological effects, such as anticancer, antiviral, antiparasitic and immunomodulatory activity, exhibiting broad biomedical application prospects. This review introduces the distribution and mechanisms of antimicrobial peptides, and summarizes the biosynthesis methods of antimicrobial peptides. We further compare and analyze the advantages and disadvantages of various antimicrobial peptide biosynthesis approaches relying on microbial expression systems and introduce new interdisciplinary peptide-design strategies based on synthetic biology. In addition, we also briefly summarize the applications of antimicrobial peptides. The application prospects of antimicrobial peptides can be classified into seven medical fields, including antiinflammatory drugs, antiviral drugs, antiparasitic drugs, anticancer drugs, medical tissue engineering, drug delivery systems, skin care and cosmetology. Furthermore, we also identify potential problems such as low expression yield, difficulty in extraction, high process cost, poor stability and insufficient biosafety of existing antimicrobial peptides. To solve these issues, computational prediction and directed gene editing technology can be used to create new antimicrobial peptides with improved antibacterial properties and reduced toxicity. It is also important to improve the industrial infrastructure of antibacterial peptide biosynthesis and develop strategies for rapid recovery of high-purity antibacterial peptides. Antimicrobial peptides can also be combined with existing antibiotics to prevent bacterial resistance to traditional antibiotics. Finally, antimicrobial peptides can be combined with new biomaterials to reduce their toxicity to tissues and organs in vivo.

Key words: antimicrobial peptide, defensin, synthetic biology, bioengineering, tissue engineering

中图分类号:

魏岱旭, 龚海伦, 张旭维. 抗菌肽的生物合成及医学应用[J]. 合成生物学, 2022, 3(4): 709-727.

Daixu WEI, Hailun GONG, Xuwei ZHANG. Biosynthesis of antimicrobial peptides and its medical application[J]. Synthetic Biology Journal, 2022, 3(4): 709-727.

图/表 7

图1 抗菌肽广泛分布于多种生物

Fig. 1 Antimicrobial peptides (AMPs) are widely distributed in many organisms

图2 阳离子型抗菌肽抗菌机制模型

Fig. 2 Antibacterial mechanisms models of cationic AMPs

表1 常见的抗菌肽生物表达系统

Tab. 1 Expression system of antimicrobial peptides in this review

Expression system and engineered microorganism	Antimicrobial peptides	References
Prokaryotic
E. coli	Cecropin	[21, 69-72]
	Perinerin	[73]
	Adenoregulin	[74]
	Abaecin	[75]
	Hep-A200	[76]
	MLH	[77]
	Hal18	[78]
	Plectasin	[79]
	Lactoferricin	[80]
	Buforin II	[81-82]
B.subtilis	Cecropin AD	[83]
	Cathelicidin-BF	[84]
	T9W	[85]
	CiMAM	[86]
Eukaryotic
S.cerevisiae	CecropinXJ	[87]
	Cecropin P1	[88]
P.pastoris	Cecropin AD	[89]
	PaDef	[90]
	Melittin	[91]
	Fowlicidin-2	[92]
	HKABF	[93]
	Mytichitin-A	[94]
	ABP-CM4	[95]
C.reinhardtii	3×Mytichitin-A	[96]
	Bacteriocin LS2	[97]
	ToAMP4	[98]
	Mytichitin-CB	[99]

图3 计算机辅助及人工智能加速新型抗菌的设计

Fig. 3 Overview of the proposed computer-assisted and AI-driven approach for accelerated novel antimicrobial peptides (AMPs) design

图4 CRISPR/Cas9基因编辑系统促进细胞分泌抗菌肽

Fig. 4 Overview of the CRISPR/Cas9 gene editing system promoting the secretion of antimicrobial peptides in mammal cells

表2 美国食品及药物管理局（FDA）批准的抗菌肽的名称、治疗的适应证、给药途径及临床试验标识号

Tab. 2 Name, indication, deliever and clinical trial identification of antimicrobial peptides approved by US Food and Drug Administration (FDA)[6, 114-116]

AMPs	Indication	Deliever	Status	Clinical trial identifiers
Daptomycin	Bacterial skin infections	Intravenous	Approved	NCT01211470
Vancomycin	Staphylococcal infections	Intravenous	Approved	NCT00175370
Dalbavancin (BI397, Dalvance, Xydalba)	Acute bacterial skin infections	Intravenous	Approved	NCT03233438
Colistin	Multidrug-resistant Gram-negative infections	Intravenous	Approved	NCT03397914

图5 抗菌肽的医学应用

Fig. 5 Medical applications of antimicrobial peptides (AMPs)

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