抗菌肽的研究现状和挑战 <sup>*</sup>

doi:10.13523/j.cb.20190812

中国生物工程杂志

2019, Vol. 39

Issue (8): 86-94 DOI: 10.13523/j.cb.20190812

综述

抗菌肽的研究现状和挑战 ^*

唐馨^1,²,毛新芳³,马彬云²,苟萍^1,^**(

)

1 新疆大学生命科学与技术学院乌鲁木齐 830046
2 南加州大学Keck医学院洛杉矶 90033
3 四川轻化工大学化学工程学院自贡 643000

Antimicrobial Peptides: Current Status and Future Challenges

TANG Xin^1,²,MAO Xin-fang³,MA Bin-yun²,GOU Ping^1,^**(

)

1 College of Life Science and Technology, Xinjiang University, ürümqi 830046, China;
2 Keck school of Medicine, University of Southern California, Los Angeles 90033, United States
3 School of Chemical Engineering, Sichuan University of Science and Engineering, Zigong 643000, China

全文: PDF(1261 KB) HTML

摘要：

抗菌肽(AMPs)广泛存在于生物体内,可以协助机体抵御外源微生物的侵害,是生物体先天性防御系统中的重要组成成分。普遍认为,抗菌肽通过膜损伤机制,破坏微生物细胞膜或细胞壁的完整性,达到抑杀微生物的目的。然而,越来越多的证据表明抗菌肽还存在非膜损伤机制,作用于胞内靶位点杀伤细胞。由于其独特的作用机制及广谱抗菌活性,抗菌肽被应用于各行各业。但是,抗菌肽的推广应用也面临着诸多难题,如生物稳定性、抗菌活性的维持和微生物耐受性等。主要对抗菌肽的种类、作用机制、微生物对抗菌肽耐受性的产生机制及抗菌肽的应用和挑战进行综述。

关键词： 抗菌肽; 非膜损伤型; 抗菌机制; 耐受性

Abstract:

Antimicrobial peptides (AMPs) are produced in various living organisms as first-line host defenses against potential pathogenic microbes in their surroundings. Pioneering studies showed that AMPs can directly interfere with the integrity of the bacterial cell membrane and cell wall though membrane-disruptive mechanism. In addition to interact with membrane, there are increasing evidence to indicate that AMPs have intracellular targets to achieve efficient killing, including nucleic acids binding, inhibiton of protein synthesis and protein-folding, inhibition of cell wall biosynthesis, inhibition of protease and cell division. Due to unique action mechanisms and broad-spectrum of activity, there are continued efforts in exploiting potential applications of AMPs in different area. However, some issues need to be resolved before AMPs be widely used, like AMPs stability, decreased antimicrobial activity and AMPs resistance. In this review, it will be mentioned that current knowledge and recent progress in AMPs action mechanisms, especially non-lytic features, mechanism of AMPs resistance and the potential problems associated with AMPs applications.

Key words: Antimicrobial peptides Non-membrane-disruptive mechanism Antibacterial mechanism Resistance

收稿日期: 2019-01-08 出版日期: 2019-09-18

ZTFLH:

Q51

基金资助: *国家自然科学基金(314605678)

通讯作者: 苟萍 E-mail: gou__ping@sina.com

	服务
	把本文推荐给朋友
	加入引用管理器
	E-mail Alert
	RSS
	作者相关文章
	唐馨
	毛新芳
	马彬云
	苟萍

引用本文:

唐馨,毛新芳,马彬云,苟萍. 抗菌肽的研究现状和挑战 ^*[J]. 中国生物工程杂志, 2019, 39(8): 86-94.

TANG Xin,MAO Xin-fang,MA Bin-yun,GOU Ping. Antimicrobial Peptides: Current Status and Future Challenges. China Biotechnology, 2019, 39(8): 86-94.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20190812 或 https://manu60.magtech.com.cn/biotech/CN/Y2019/V39/I8/86

图1 抗菌肽的作用机制示意图

[1]	Steiner H, Hultmark D, Engstr?m ? , et al. Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature, 1981,292(5820):246-248.
[2]	Zasloff M . Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proc Natl Acad Sci USA, 1987,84:5449-5453.
[3]	Zasloff M . Antimicrobial peptides of multicellular organisms. Nature, 2002,415(6870):389-395.
[4]	Le C F, Fang C M, Sekaran S D . Beyond membrane-lytic: intracellular targeting mechanisms by antimicrobial peptides. Antimicrobial Agents and Chemotherapy, 2017,61(4):e02340-16.
[5]	Brogden K A . Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nature Reviews Microbiology, 2005,3(3):238-250.
[6]	Wang Y D, Kung C W, Chen J Y . Antiviral activity by fish antimicrobial peptides of epinecidin-1 and hepcidin 1-5 against nervous necrosis virus in medaka. Peptides, 2010,31(6):1026-1033. doi: 10.1016/j.peptides.2010.02.025
[7]	Lupetti A, Van Dissel J, Brouwer C , et al. Human antimicrobial peptides’ antifungal activity against Aspergillus fumigatus. European Journal of Clinical Microbiology &Infectious Diseases, 2008,27(11):1125-1129.
[8]	Vizioli J, Salzet M . Antimicrobial peptides versus parasitic infections? Trends in Parasitology, 2002,18(11):475-476.
[9]	Hoskin D W, Ramamoorthy A . Studies on anticancer activities of antimicrobial peptides. Biochimica et Biophysica Acta (BBA)-Biomembranes, 2008,1778(2):357-375.
[10]	Amer L S, Bishop B M, van Hoek M L . Antimicrobial and antibiofilm activity of cathelicidins and short, synthetic peptides against Francisella. Biochemical and Biophysical Research Communications, 2010,396(2):246-251.
[11]	Hilchie A L, Wuerth K, Hancock R E . Immune modulation by multifaceted cationic host defense (antimicrobial) peptides. Nature Chemical Biology, 2013,9(12):761-768. doi: 10.1038/NCHEMBIO.1393
[12]	Wang G, Li X, Wang Z . APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Research, 2015,44(D1):D1087-D1093.
[13]	Fan L, Sun J, Zhou M , et al. DRAMP: a comprehensive data repository of antimicrobial peptides. Scientific Reports, 2016,6:24482.
[14]	Di Luca M, Maccari G, Maisetta G , et al. BaAMPs: the database of biofilm-active antimicrobial peptides. Biofouling, 2015,31(2):193-199.
[15]	Wang G . Improved methods for classification, prediction, and design of antimicrobial peptides. Computational Peptidology, 2015, 43-66.
[16]	Meneguetti B T, Machado L d S, Oshiro K G , et al. Antimicrobial peptides from fruits and their potential use as biotechnological tools-a review and outlook. Frontiers in Microbiology, 2017,7:2136.
[17]	Wang G . Antimicrobial peptides: discovery, design and novel therapeutic strategies. 2 nd ed . UK: CABI, 2017: 1-261.
[18]	Scocchi M, Mardirossian M, Runti G , et al. Non-membrane permeabilizing modes of action of antimicrobial peptides on bacteria. Current Topics in Medicinal Chemistry, 2016,16(1):76-88.
[19]	Gaspar D, Veiga A S, Castanho M A . From antimicrobial to anticancer peptides. A review. Frontiers in Microbiology, 2013,4:294.
[20]	Reddy K, Yedery R, Aranha C . Antimicrobial peptides: premises and promises. International Journal of Antimicrobial Agents, 2004,24(6):536-547. doi: 10.1016/j.ijantimicag.2004.09.005
[21]	Yang L, Harroun T A, Weiss T M , et al. Barrel-stave model or toroidal model? A case study on melittin pores. Biophysical Journal, 2001,81(3):1475-1485. doi: 10.1016/S0006-3495(01)75802-X
[22]	Wu M, Maier E, Benz R , et al. Mechanism of interaction of different classes of cationic antimicrobial peptides with planar bilayers and with the cytoplasmic membrane of Escherichia coli. Biochemistry, 1999,38(22):7235-7242.
[23]	Sengupta D, Leontiadou H, Mark A E , et al. Toroidal pores formed by antimicrobial peptides show significant disorder. Biochimica et Biophysica Acta (BBA)-Biomembranes, 2008,1778(10):2308-2317.
[24]	Bechinger B, Gorr S U . Antimicrobial peptides: mechanisms of action and resistance. Journal of Dental Research, 2017,96(3):254-260.
[25]	Choi H, Rangarajan N, Weisshaar J C . Lights, camera, action! Antimicrobial peptide mechanisms imaged in space and time. Trends in Microbiology, 2016,24(2):111-122.
[26]	Patrzykat A, Friedrich C L, Zhang L , et al. Sublethal concentrations of pleurocidin-derived antimicrobial peptides inhibit macromolecular synthesis in Escherichia coli. Antimicrobial Agents and Chemotherapy, 2002,46(3):605-614.
[27]	Schneider T, Kruse T, Wimmer R , et al. Plectasin, a fungal defensin, targets the bacterial cell wall precursor Lipid II. Science, 2010,328(5982):1168-1172.
[28]	Yount N Y, Bayer A S, Xiong Y Q , et al. Advances in antimicrobial peptide immunobiology. Peptide Science: Original Research on Biomolecules, 2006,84(5):435-458.
[29]	Lan Y, Ye Y, Kozlowska J , et al. Structural contributions to the intracellular targeting strategies of antimicrobial peptides. Biochimica et Biophysica Acta (BBA)-Biomembranes, 2010,1798(10):1934-1943.
[30]	Gottschalk S, Thomsen L E . The interaction of antimicrobial peptides with the membrane and intracellular targets of Staphylococcus aureus investigated by ATP leakage, DNA-binding analysis, and the expression of a LexA-controlled gene, recA. Antimicrobial Peptides, 2017, 297-305.
[31]	Sharma A, Pohane A A, Bansal S , et al. Cell penetrating synthetic antimicrobial peptides (SAMPs) exhibiting potent and selective killing of Mycobacterium by targeting its DNA. Chemistry-A European Journal, 2015,21(9):3540-3545.
[32]	Scocchi M, Tossi A, Gennaro R . Proline-rich antimicrobial peptides: converging to a non-lytic mechanism of action. Cellular and Molecular Life Sciences, 2011,68(13):2317-2330. doi: 10.1007/s00018-011-0721-7
[33]	Boman H G, Agerberth B, Boman A . Mechanisms of action on Escherichia coli of cecropin P1 and PR-39, two antibacterial peptides from pig intestine. Infection and Immunity, 1993,61(7):2978-2984.
[34]	Otvos L, O I, Rogers M E , et al. Interaction between heat shock proteins and antimicrobial peptides. Biochemistry, 2000,39(46):14150-14159.
[35]	Kragol G, Lovas S, Varadi G , et al. The antibacterial peptide pyrrhocoricin inhibits the ATPase actions of DnaK and prevents chaperone-assisted protein folding. Biochemistry, 2001,40(10):3016-3026.
[36]	Chesnokova L S, Slepenkov S V, Witt S N . The insect antimicrobial peptide, l-pyrrhocoricin, binds to and stimulates the ATPase activity of both wild-type and lidless DnaK. FEBS Letters, 2004,565(1-3):65-69.
[37]	Koch A L . Bacterial wall as target for attack past, present, and future research. Clinical Microbiology Reviews, 2003,16(4):673-687.
[38]	Essig A, Hofmann D, Münch D , et al. Copsin, a novel peptide-based fungal antibiotic interfering with the peptidoglycan synthesis. Journal of Biological Chemistry, 2014: jbc. M114. 599878.
[39]	Br?t z H, Bierbaum G, Leopold K , et al. The lantibiotic mersacidin inhibits peptidoglycan synthesis by targeting lipid II. Antimicrobial Agents and Chemotherapy, 1998,42(1):154-160.
[40]	Breukink E, Kruijff B . Lipid II as a target for antibiotics. Nature Reviews Drug Discovery, 2006,5(4):321-323.
[41]	Gusman H, Grogan J, Kagan H M , et al. Salivary histatin 5 is a potent competitive inhibitor of the cysteine proteinase clostripain. FEBS Letters, 2001,489(1):97-100.
[42]	Puri S, Edgerton M . How does it kill-understanding the candidacidal mechanism of salivary Histatin 5. Eukaryotic Cell, 2014,13(8):958-964. doi: 10.1128/EC.00095-14
[43]	Pratt Z L, Chen B, Czuprynski C J , et al. Characterization of osmotic-induced filaments of Salmonella enterica. Applied and Environmental Microbiology, 2012,78(18):6704-6713. doi: 10.1128/AEM.01784-12
[44]	Ishikawa M, Kubo T, Natori S . Purification and characterization of a diptericin homologue from Sarcophaga peregrina (flesh fly). Biochemical Journal, 1992,287(2):573-578.
[45]	Bi E, Lutkenhaus J . Cell division inhibitors SulA and MinCD prevent formation of the FtsZ ring. Journal of Bacteriology, 1993,175(4):1118-1125.
[46]	Yadavalli S S, Carey J N, Leibman R S , et al. Antimicrobial peptides trigger a division block in Escherichia coli through stimulation of a signalling system. Nature Communications, 2016,7:12340.
[47]	Ho Y H, Shah P, Chen Y W , et al. Systematic analysis of intracellular-targeting antimicrobial peptides, bactenecin 7, hybrid of pleurocidin and dermaseptin, proline-arginine-rich peptide, and lactoferricin B, by using Escherichia coli proteome microarrays. Molecular & Cellular Proteomics 2016: mcp. M115. 054999.
[48]	Gunn J S, Ryan S S, Van Velkinburgh J C , et al. Genetic and functional analysis of a PmrA-PmrB-regulated locus necessary for lipopolysaccharide modification, antimicrobial peptide resistance, and oral virulence of Salmonella enterica serovar typhimurium. Infection and Immunity, 2000,68(11):6139-6146.
[49]	Andersson D I, Hughes D, Kubicek-Sutherland J Z . Mechanisms and consequences of bacterial resistance to antimicrobial peptides. Drug Resistance Updates, 2016,26:43-57.
[50]	Lofton H, Anwar N, Rhen M , et al. Fitness of Salmonella mutants resistant to antimicrobial peptides. Journal of Antimicrobial Chemotherapy, 2014,70(2):432-440.
[51]	Sun S, Negrea A, Rhen M , et al. Genetic analysis of colistin resistance in Salmonella enterica serovar typhimurium. Antimicrobial Agents and Chemotherapy, 2009,53(6):2298-2305.
[52]	Moffatt J H, Harper M, Harrison P , et al. Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrobial Agents and Chemotherapy, 2010,54(12):4971-4977.
[53]	Chikindas M L, Weeks R, Drider D , et al. Functions and emerging applications of bacteriocins. Current Opinion in Biotechnology, 2018,49:23-28.
[54]	Santos J C P, Sousa R C S, Otoni C G , et al. Nisin and other antimicrobial peptides: production, mechanisms of action, and application in active food packaging. Innovative Food Science & Emerging Technologies, 2018,48:179-194.
[55]	Dutta P, Das S . Mammalian antimicrobial peptides: promising therapeutic targets against infection and chronic inflammation. Current Topics in Medicinal Chemistry, 2016,16(1):99-129.
[56]	Landman D, Georgescu C, Martin D A , et al. Polymyxins revisited. Clinical Microbiology Reviews, 2008,21(3):449-465.
[57]	Marr A K, Gooderham W J, Hancock R E . Antibacterial peptides for therapeutic use: obstacles and realistic outlook. Current Opinion in Pharmacology, 2006,6(5):468-472. doi: 10.1016/j.coph.2006.04.006
[58]	da Silva Malheiros P, Daroit D J, Brandelli A . Food applications of liposome-encapsulated antimicrobial peptides. Trends in Food Science & Technology, 2010,21(6):284-292.
[59]	Keymanesh K, Soltani S, Sardari S . Application of antimicrobial peptides in agriculture and food industry. World Journal of Microbiology and Biotechnology, 2009,25(6):933-944.
[60]	Kokoza V, Ahmed A, Cho W L , et al. Engineering blood meal-activated systemic immunity in the yellow fever mosquito, Aedes aegypti. Proceedings of the National Academy of Sciences, 2000,97(16):9144-9149.
[61]	Kokoza V, Ahmed A, Shin S W , et al. Blocking of Plasmodium transmission by cooperative action of Cecropin A and Defensin A in transgenic Aedes aegypti mosquitoes. Proceedings of the National Academy of Sciences, 2010,107(18):8111-8116.
[62]	Kerr D E, Plaut K, Bramley A J , et al. Lysostaphin expression in mammary glands confers protection against staphylococcal infection in transgenic mice. Nature Biotechnology, 2001,19(1):66-70.
[63]	Fan W, Plaut K, Bramley A , et al. Adenoviral-mediated transfer of a lysostaphin gene into the goat mammary gland. Journal of Dairy Science, 2002,85(7):1709-1716. doi: 10.3168/jds.S0022-0302(02)74244-6
[64]	王曦, 陈熙明, 浦铜良 . 溶葡球菌酶高效表达与应用. 中国生物工程杂志 2017,37(9):118-125.
	Wang X, Chen X M, Pu T L . Progress on high efficient expression and application of lysostaphin. China Biotechnology 2017,37(9):118-125.
[65]	Sousa D A, Mulder K C, Nobre K S , et al. Production of a polar fish antimicrobial peptide in Escherichia coli using an ELP-intein tag. Journal of Biotechnology, 2016,234:83-89.
[66]	Tang X . Elastin-like polypeptides as thermosensitive polymer system. Advanced Materials Research, 2014,898:296-299.
[67]	Paria A, Vinay T, Gupta S K , et al. Antimicrobial peptides: a promising future alternative to antibiotics in aquaculture. World Aquculture, 2018: 67-69.
[68]	Cheng A C, Lin H L, Shiu Y L , et al. Isolation and characterization of antimicrobial peptides derived from Bacillus subtilis E20-fermented soybean meal and its use for preventing Vibrio infection in shrimp aquaculture. Fish Shellfish Immunology, 2017,67:270-279.
[69]	Lai Y, Gallo R L . AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends in Immunology, 2009,30(3):131-141. doi: 10.1016/j.it.2008.12.003
[70]	唐馨, 王慧, 热西力 , 等. 新疆家蚕抗菌肽在毕赤酵母中表达及活性研究. 生物技术, 2011,21(2):26-31.
	Tang X, Wang H, Kelaimu R X L , et al. Molecular cloning, expression of Cecropin -XJ gene from silkworm and antibacterial activity in Pichia pastoris. Biotechnology, 2011,21(2):26-31.
[71]	唐馨, 毛新芳, 热西力 , 等. 黄粉虫抗菌肽 TmAMP3 在大肠杆菌中的高效表达及活性检测. 昆虫学报, 2011,54(10):1111-1117.
	Tang X, Mao X F, Kelaimu R X L , et al. High-level expression and function assay of antimicrobiol peptide TmAMP3 of Tenebrio molitor (Tenebrionidae, Coleoptera) in Escherichia coli. Acta Entomologica Sinica, 2011,54(10):1111-1117.
[72]	Yeaman M R, Yount N Y . Mechanisms of antimicrobial peptide action and resistance. Pharmacological Reviews, 2003,55(1):27-55.

[1]	邓蕊,曾佳利,卢雪梅. 基于Musca domestica cecropin的抗肿瘤小分子衍生肽筛选及构效关系解析^*[J]. 中国生物工程杂志, 2021, 41(11): 14-22.
[2]	杨隆兵,国果,马慧玲,李妍,赵欣宇,苏佩佩,张勇. 家蝇抗菌肽AMPs17蛋白原核表达条件的优化及其抗真菌活性检测 ^*[J]. 中国生物工程杂志, 2019, 39(4): 24-31.
[3]	唐健雪,肖永乐,彭俊杰,赵世纪,万小平,高荣. 融合抗菌肽基因在重组毕赤酵母的表达及体外活性研究 ^*[J]. 中国生物工程杂志, 2018, 38(6): 9-16.
[4]	戈家傲,刘畅,龚建刚,刘艳琴. 抗菌环肽的研究进展 ^*[J]. 中国生物工程杂志, 2018, 38(11): 76-83.
[5]	杨静,贾如涵,李文慧,石大林,邵明洋,韩跃武. 抗菌肽改良设计及抗炎作用的研究进展[J]. 中国生物工程杂志, 2018, 38(1): 57-61.
[6]	马泽林, 刘家亨, 黄序, 财音青格乐, 朱宏吉. 微生物利用木质纤维素的研究进展[J]. 中国生物工程杂志, 2017, 37(6): 124-133.
[7]	程可利, 刘晓, 李素霞. 对SDS稳定的V8(V125T)蛋白酶突变体的高效表达及性质研究[J]. 中国生物工程杂志, 2017, 37(4): 56-67.
[8]	温赛, 刘怀然, 韩煦, 李天, 邢旋. 综述人工合成型抗菌肽及其药学应用研究进展[J]. 中国生物工程杂志, 2016, 36(8): 89-98.
[9]	曹莹莹, 邓盾, 张云, 孙爱君, 夏方亮, 胡云峰. 南海深海新颖低温脂肪酶的克隆、表达及酶学性质鉴定[J]. 中国生物工程杂志, 2016, 36(3): 43-52.
[10]	刘晓明, 姜宁, 张爱忠, 蔡鹏. 杂合抗菌肽在毕赤酵母中的表达及其活性测定[J]. 中国生物工程杂志, 2016, 36(2): 81-89.
[11]	巫春旭, 卢雪梅, 金小宝, 朱家勇. 天蚕素类抗菌肽分子设计研究进展[J]. 中国生物工程杂志, 2016, 36(2): 96-100.
[12]	公颜慧, 马三梅, 张云, 王永飞, 胡云峰. 新颖微生物低温酯酶EstP8的酶学性质研究与在手性催化中的应用[J]. 中国生物工程杂志, 2016, 36(10): 35-44.
[13]	陈洁梅, 张灿辉, 艾田. 解淀粉芽孢杆菌KN-BL-1及其发酵豆粕产抗菌肽类物质的研究[J]. 中国生物工程杂志, 2014, 34(10): 61-66.
[14]	武如娟, 张日俊. 杂合抗菌肽设计及生物学活性的研究进展[J]. 中国生物工程杂志, 2013, 33(9): 94-100.
[15]	陈宇婷, 王长海, 严秀文, 黎军胜. 抗菌肽的设计及其应用[J]. 中国生物工程杂志, 2013, 33(7): 97-102.

Viewed

Full text

Abstract

Cited

Shared

Discussed