抗生物膜肽研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2020-0577

摘要/Abstract

摘要：

细菌生物膜导致的细菌耐药性增加受到了广泛关注。抗生物膜肽是一类具有抑制和杀灭细菌生物膜独特优势的抗微生物肽,有望成为理想的抗细菌生物膜的新型抗菌药物。就抗生物膜肽与生物膜各组分间的相互作用、抗生物膜肽对生物膜形成的干预作用及其调控、抗生物膜肽目前存在的问题及其解决思路以及抗生物膜肽未来的应用领域等展开综述。

关键词: 细菌生物膜, 抗生物膜肽, 相互作用

Abstract:

The increase in bacterial resistance caused by bacterial biofilms has received widespread attention. Anti-biofilm peptides are a class of antimicrobial peptides with unique advantages in inhibiting and killing bacterial biofilms,and are expected to become ideal new antibacterial drugs against bacterial biofilms. This paper mainly reviews how anti-biofilm peptides interact with biofilm components,the intervention and regulation of anti-biofilm peptides on biofilm formation,the current issues of anti-biofilm peptides and solutions,and the future applications of anti-biofilm peptides.

Key words: bacterial biofilm, anti-biofilm peptide, interaction

张阳, 程鹏, 李晓芬, 陈红伟. 抗生物膜肽研究进展[J]. 生物技术通报, 2021, 37(2): 216-223.

ZHANG Yang, CHENG Peng, LI Xiao-fen, CHEN Hong-wei. Research Progress on Anti-biofilm Peptides[J]. Biotechnology Bulletin, 2021, 37(2): 216-223.

图/表 1

参考文献 51

[1]	Hashem YA, Amin HM, Essam TM, et al. Biofilm formation in enterococci:Genotype-phenotype correlations and inhibition by vancomycin[J]. Scientific Reports, 2017,7(1):5733. doi: 10.1038/s41598-017-05901-0 URL pmid: 28720810
[2]	Haney EF, Trimble MJ, Cheng JT, et al. Critical assessment of methods to quantify biofilm growth and evaluate antibiofilm activity of host defence peptides[J]. Biomolecules, 2018,8(2):29.
[3]	Overhage J, Campisano A, Bains M, et al. Human host defense peptide LL-37 prevents bacterial biofilm formation[J]. Infection and Immunity, 2008,76(9):4176-4182. URL pmid: 18591225
[4]	Skariyachan S, Sridhar VS, Packirisamy S, et al. Recent perspectives on the molecular basis of biofilm formation by Pseudomonas aeruginosa and approaches for treatment and biofilm dispersal[J]. Folia Microbiologica, 2018,63(4):413-432. doi: 10.1007/s12223-018-0585-4 URL pmid: 29352409
[5]	Gowrishankar S, Pandian SK. Modulation of Staphylococcus epidermidis(RP62A)extracellular polymeric layer by marine cyclic dipeptide-cyclo(l-leucyl-l-prolyl)thwarts biofilm formation[J]. Biochim Biophys Acta, 2017,1859(7):1254-1262.
[6]	Duperthuy M, Sjostrom AE, Sabharwal D, et al. Role of the Vibrio cholerae matrix protein Bap1 in cross-resistance to antimicrobial peptides[J]. PLoS Pathog, 2013,9(10):e1003620. doi: 10.1371/journal.ppat.1003620 URL pmid: 24098113
[7]	Akeel RA, Mateen A, Syed R. An alanine-rich peptide attenuates quorum sensing-regulated virulence and biofilm formation in Staphylococcus aureus[J]. Journal of AOAC International, 2019,102(4):1228-1234. doi: 10.5740/jaoacint.18-0251 URL pmid: 30446019
[8]	Cuzzi B, Herasimenka Y, Silipo A, et al. Versatility of the Burk-holderia cepacia complex for the biosynjournal of exopolysaccharides:A comparative structural investigation[J]. PLoS One, 2014,9(4):e94372. doi: 10.1371/journal.pone.0094372 URL pmid: 24722641
[9]	Benincasa M, Lagatolla C, Dolzani L, et al. Biofilms from Klebsiella pneumoniae:Matrix polysaccharide structure and interactions with antimicrobial peptides[J]. Microorganisms, 2016,4(3):26.
[10]	Pulido D, Prats-Ejarque G, Villalba C, et al. A novel RNase 3/ECP peptide for Pseudomonas aeruginosa biofilm eradication that combines antimicrobial, lipopolysaccharide binding, and Cell-Agglutinating activities[J]. Antimicrob Agents Chemother, 2016,60(10):6313-6325. URL pmid: 27527084
[11]	Vuong C, Voyich JM, Fischer ER, et al. Polysaccharide intercellular adhesin(PIA)protects Staphylococcus epidermidis against major components of the human innate immune system[J]. Cell Microbiol, 2004,6(3):269-275. doi: 10.1046/j.1462-5822.2004.00367.x URL pmid: 14764110
[12]	Wilton M, Charron-Mazenod L, Moore R, et al. Extracellular DNA acidifies biofilms and induces aminoglycoside resistance in Pseudomonas aeruginosa[J]. Antimicrob Agents Chemother, 2016,60(1):544-553. doi: 10.1128/AAC.01650-15 URL pmid: 26552982
[13]	Palchevskiy V, Finkel SE. Escherichia coli competence gene homologs are essential for competitive fitness and the use of DNA as a nutrient[J]. J Bacteriol, 2006,188(11):3902-3910. doi: 10.1128/JB.01974-05 URL pmid: 16707682
[14]	Johnson L, Horsman SR, et al. Extracellular DNA-induced antimicrobial peptide resistance in Salmonella enterica serovar Typhimurium[J]. BMC Microbiol, 2013,13:115. doi: 10.1186/1471-2180-13-115 URL pmid: 23705831
[15]	Wang SY, Han DC, Song C, et al. Membrane biofouling retardation by zwitterionic peptide and its impact on the bacterial adhesion[J]. Environmental Science and Pollution Research, 2019,26(16):16674-16681. doi: 10.1007/s11356-019-04898-5 URL pmid: 30989603
[16]	Lewenza S. Extracellular DNA-induced antimicrobial peptide resistance mechanisms in Pseudomonas aeruginosa[J]. Front Microbiol, 2013,4:21. doi: 10.3389/fmicb.2013.00021 URL pmid: 23419933
[17]	Batoni G, Maisetta G, Esin S. Antimicrobial peptides and their interaction with biofilms of medically relevant bacteria[J]. Biochim Biophys Acta, 2016,1858(5):1044-1060. doi: 10.1016/j.bbamem.2015.10.013 URL pmid: 26525663
[18]	Wood TK, Knabel SJ, Kwan BW. Bacterial persister cell formation and dormancy[J]. Applied and Environmental Microbiology, 2013,79(23):7116-7121. URL pmid: 24038684
[19]	Wang G, Mishra B, Epand RF, et al. High-quality 3D structures shine light on antibacterial, anti-biofilm and antiviral activities of human cathelicidin LL-37 and its fragments[J]. Biochim Biophys Acta, 2014,1838(9):2160-2172. doi: 10.1016/j.bbamem.2014.01.016 URL pmid: 24463069
[20]	De Brucker K, Delattin N, Robijns S, et al. Derivatives of the mouse Cathelicidin-Related antimicrobial peptide(CRAMP)inhibit fungal and bacterial biofilm formation[J]. Antimicrobial Agents and Chemotherapy, 2014,58(9):5395-5404. doi: 10.1128/AAC.03045-14 URL pmid: 24982087
[21]	Chen HW, Wubbolts RW, Haagsman HP, et al. Inhibition and eradication of Pseudomonas aeruginosa biofilms by host defence peptides[J]. Scientific Reports, 2018,8(1):10446. doi: 10.1038/s41598-018-28842-8 URL pmid: 29993029
[22]	Mwangi J, Yin Y, Wang G, et al. The antimicrobial peptide ZY4 combats multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii infection[J]. Proceedings of the National Academy of Sciences, 2019,116(52):26516-26522.
[23]	Paulone S, Ardizzoni A, Tavanti A, et al. The synthetic killer peptide KP impairs Candida albicans biofilm in vitro[J]. PLoS One, 2017,12(7):e0181278. doi: 10.1371/journal.pone.0181278 URL pmid: 28704490
[24]	Rasamiravaka T, Labtani Q, Duez P, et al. The formation of biofilms by Pseudomonas aeruginosa:A review of the natural and synthetic compounds interfering with control mechanisms[J]. BioMed Research International, 2015,2015:759348. doi: 10.1155/2015/759348 URL pmid: 25866808
[25]	Scarsini M, Tomasinsig L, Arzese A, et al. Antifungal activity of cathelicidin peptides against planktonic and biofilm cultures of Candida species isolated from vaginal infections[J]. Peptides, 2015,71:211-221. doi: 10.1016/j.peptides.2015.07.023 URL pmid: 26238597
[26]	Yu Z, Kong Y, Luo Z, et al. Anti-bacterial activity of mutant chensinin-1 peptide against multidrug-resistant Pseudomonas aeruginosa and its effects on biofilm-associated gene expression[J]. Experimental and Therapeutic Medicine, 2019,17(3):2031-2038. doi: 10.3892/etm.2019.7182 URL pmid: 30867692
[27]	Sethupathy S, Prasath KG, Ananthi S, et al. Proteomic analysis reveals modulation of iron homeostasis and oxidative stress response in Pseudomonas aeruginosa PAO1 by curcumin inhibiting quorum sensing regulated virulence factors and biofilm production[J]. Journal of Proteomics, 2016,145:112-126. URL pmid: 27108548
[28]	Taha MN, Saafan AE, Ahmedy A, et al. Two novel synthetic peptides inhibit quorum sensing-dependent biofilm formation and some virulence factors in Pseudomonas aeruginosa PAO1[J]. Journal of Microbiology, 2019,57(7):618-625.
[29]	Ciulla M, Di Stefano A, Marinelli L, et al. RNAIII inhibiting peptide(RIP)and derivatives as potential tools for the treatment of S. aureus biofilm infections[J]. Current Topics in Medicinal Chemistry, 2018,18(24):2068-2079. doi: 10.2174/1568026618666181022120711 URL pmid: 30345922
[30]	Chua SL, Hultqvist LD, Yuan M, et al. In vitro and in vivo generation and characterization of Pseudomonas aeruginosa biofilm-dispersed cells via c-di-GMP manipulation[J]. Nature Protocols, 2015,10(8):1165-1180. URL pmid: 26158442
[31]	Whitney JC, Whitfield GB, Marmont LS, et al. Dimeric c-di-GMP is required for post-translational regulation of alginate production in Pseudomonas aeruginosa[J]. The Journal of Biological Chemistry, 2015,290(20):12451-12462. doi: 10.1074/jbc.M115.645051 URL pmid: 25817996
[32]	Foletti C, Kramer RA, et al. Functionalized Proline-Rich peptides bind the bacterial second messenger c-di-GMP[J]. Angewandte Chemie-International Edition, 2018,57(26):7729-7733. URL pmid: 29521445
[33]	何佳彧, 梁菊, 宣茂松, 等. 提高多肽体内稳定性的有效策略[J]. 药学学报, 2020,55(1):25-32.
	He JY, Liang Y, Xuan MS, et al. Effective strategies for improving the stability of peptides in vivo[J]. Acta Pharmaceutica Sinica, 2020,55(1):25-32
[34]	Kang HK, Seo CH, Luchian T, et al. Pse-T2, an antimicrobial peptide with high-level, broad-spectrum antimicrobial potency and skin biocompatibility against multidrug-resistant Pseudomonas aeru-ginosa infection[J]. Antimicrobial Agents and Chemotherapy, 2018,62(12):e01493-18. doi: 10.1128/AAC.01493-18 URL pmid: 30323036
[35]	Yu ZJ, Deslouches B, Walton WG, et al. Enhanced biofilm prevention activity of a SPLUNC1-derived antimicrobial peptide against Staphylococcus aureus[J]. PLoS One, 2018,13(9):e0203621. URL pmid: 30216370
[36]	Kłodzińska SN, Pletzer D, Rahanjam N, et al. Hyaluronic acid-based nanogels improve in vivo compatibility of the anti-biofilm peptide DJK-5[J]. Nanomedicine:Nanotechnology, Biology and Medicine, 2019,20:102022.
[37]	陈红伟, 李英伦, 刘娟, 等. 抗菌肽的临床应用与内源性表达调控研究进展[J]. 生物技术通报, 2014(4):25-29.
	Chen HW, Li YL, Liu J, et al. Progress on antimicrobial peptides’gene endogenous expression regulation and clinical application[J]. Biotechnology Bulletin, 2014(4):25-29.
[38]	张志强, 黄庆洲, 李英伦, 等. 抗菌肽重组表达体系及基因表达调控研究进展[J]. 中国兽医杂志, 2013,49(7):58-60.
	Zhang ZQ, Huang QZ, Li YL, et al. The progress on antimicrobial peptides’gene expression system and regulation[J]. Chinese Journal of Veterinary Medicine, 2013,49(7):58-60.
[39]	Dosler S, Mataraci E. In vitro pharmacokinetics of antimicrobial cationic peptides alone and in combination with antibiotics against methicillin resistant Staphylococcus aureus biofilms[J]. Peptides, 2013,49:53-58. doi: 10.1016/j.peptides.2013.08.008 URL pmid: 23988790
[40]	Dosler S, Karaaslan E. Inhibition and destruction of Pseudomonas aeruginosa biofilms by antibiotics and antimicrobial peptides[J]. Peptides, 2014,62:32-37. doi: 10.1016/j.peptides.2014.09.021 URL pmid: 25285879
[41]	Lashua LP, Melvin JA, Deslouches B, et al. Engineered cationic antimicrobial peptide(eCAP)prevents Pseudomonas aeruginosa biofilm growth on airway epithelial cells[J]. Journal of Antimicrobial Chemotherapy, 2016,71(8):2200-2207.
[42]	Martinez M, Gonçalves S, Felício MR, et al. Synergistic and antibiofilm activity of the antimicrobial peptide P5 against carbapenem-resistant Pseudomonas aeruginosa[J]. BBA - Biomembranes, 2019,1861(7):1329-1337. doi: 10.1016/j.bbamem.2019.05.008 URL pmid: 31095945
[43]	Mnif S, Jardak M, Graiet I, et al. The novel cationic cell-penetrating peptide PEP-NJSM is highly active against Staphylococcus epidermidis biofilm[J]. International Journal of Biological Macromolecules, 2019,125:262-269. doi: 10.1016/j.ijbiomac.2018.12.008 URL pmid: 30521892
[44]	Mansour SC, de la Fuente-Núñez C, Hancock REW. Peptide IDR-1018:Modulating the immune system and targeting bacterial biofilms to treat antibiotic-resistant bacterial infections[J]. Journal of Peptide Science, 2015,21(5):323-329. doi: 10.1002/psc.2708 URL pmid: 25358509
[45]	Molhoek EM, van Dijk A, Veldhuizen EJA, et al. A cathelicidin-2-derived peptide effectively impairs Staphylococcus epidermidis biofilms[J]. Int J Antimicrob Agents, 2011,37(5):476-479. URL pmid: 21376541
[46]	Jannadi H, Correa W, et al. Antimicrobial peptides Pep19-2. 5 and Pep19-4LF inhibit Streptococcus mutans growth and biofilm formation[J]. Microbial Pathogenesis, 2019,133:103546. doi: 10.1016/j.micpath.2019.103546 URL pmid: 31112769
[47]	Geng H, Yuan Y, Adayi A, et al. Engineered chimeric peptides with antimicrobial and titanium-binding functions to inhibit biofilm formation on Ti implants[J]. Mater Sci Eng C Mater Biol Appl, 2018,82:141-154. URL pmid: 29025642
[48]	Basak A, Abouelhassan Y, Zuo R, et al. Antimicrobial peptide-inspired NH125 analogues:Bacterial and fungal biofilm-eradicating agents and rapid killers of MRSA persisters[J]. Org Biomol Chem, 2017,15(26):5503-5512. doi: 10.1039/c7ob01028a URL pmid: 28534905
[49]	Agrillo B, Balestrieri M, Gogliettino M, et al. Functionalized polymeric materials with Bio-Derived antimicrobial peptides for “active” packaging[J]. International Journal of Molecular Sciences, 2019,20(3):601.
[50]	Doiron K, Beaulieu L, St-Louis R, et al. Reduction of bacterial biofilm formation using marine natural antimicrobial peptides[J]. Colloids and Surfaces B:Biointerfaces, 2018,167:524-530. URL pmid: 29729630
[51]	Shah MS, Qureshi S, Kashoo Z, et al. Methicillin resistance genes and in vitro biofilm formation among Staphylococcus aureus isolates from bovine mastitis in India[J]. Comparative Immunology, Microbiology and Infectious Diseases, 2019,64:117-124. doi: 10.1016/j.cimid.2019.02.009 URL pmid: 31174686

名称	影响阶段	作用的菌株	来源	作用方式	文献
LL-37 LL-37衍生物	黏附阶段形成阶段成熟阶段	大肠杆菌铜绿假单胞菌鲍曼不动杆菌	人	杀灭浮游菌;抑制生物膜形成;某些衍生物（如KS-30）能破坏生物膜结构	[19]
SPLUNC1-α4M1	形成阶段	金黄色葡萄球菌	人	抑制生物膜形成	[35]
RN3（5-17P22-36）	成熟阶段	铜绿假单胞菌	人源衍生物	清除成熟生物膜;杀灭生物膜细菌	[10]
PEP-NJSM	黏附阶段形成阶段成熟阶段	表皮葡萄球菌	人病毒蛋白组	减少原始细菌黏附;抑制生物膜细菌活性;提高生物膜细菌死亡率	[43]
IDR-1018	形成阶段成熟阶段	粪肠球菌金黄色葡萄球菌铜绿假单胞菌鲍曼不动杆菌	牛	清除成熟生物膜;提高抗生素或者抗微生物肽的抗生物膜能力	[44]
BMAP-28	黏附阶段	白色念珠菌	牛	杀灭浮游细菌	[25]
CRAMP	成熟阶段	铜绿假单胞菌	鼠	清除成熟生物膜	[21]
P318	形成阶段	白色念珠菌大肠杆菌铜绿假单胞菌	鼠源衍生物	抑制生物膜细菌活性	[20]
Cath-2	黏附阶段成熟阶段	表皮葡萄球菌	鸡	减少原始细菌黏附;杀灭生物膜细菌	[45]
MC1	形成阶段	铜绿假单胞菌	蛙源衍生物	下调Pel、AlgD和Psl基因抑制多糖合成	[26]
PT13	形成阶段	金黄色葡萄球菌	胡杨	抑制细胞粘附和粘附蛋白编码基因表达	[7]
CLP	形成阶段成熟阶段	表皮葡萄球菌	淀粉芽孢杆菌	降低EPS组分（多糖、蛋白质、eDNA）;破坏EPS结构	[5]
Nisin	形成阶段	铜绿假单胞菌	乳酸链球菌	降低生物膜多糖、eDNA含量;减少原始细菌黏附	[15]
Pep19-2.5	形成阶段	变异链球菌	人工合成	抑制细菌生长活性	[46]
P5	形成阶段	铜绿假单胞菌	人工合成	破坏生物膜结构;杀灭生物膜细菌	[42]
ZY4	成熟阶段	铜绿假单胞菌	人工合成	清除成熟生物膜和杀灭持留菌	[22]
KP	形成阶段成熟阶段	白色念珠菌	人工合成	破坏生物膜结构;抑制生物膜形成相关基因表达	[23]
LIVRHK;LIVRRK	形成阶段	铜绿假单胞菌	人工合成	抑制了Lasl/R和Rhl/R的表达;抑制毒力因子产生	[28]
WLBU2	形成阶段	铜绿假单胞菌	人工合成	抑制生物膜形成	[41]

名称	影响阶段	作用的菌株	来源	作用方式	文献
LL-37 LL-37衍生物	黏附阶段形成阶段成熟阶段	大肠杆菌铜绿假单胞菌鲍曼不动杆菌	人	杀灭浮游菌;抑制生物膜形成;某些衍生物（如KS-30）能破坏生物膜结构	[19]
SPLUNC1-α4M1	形成阶段	金黄色葡萄球菌	人	抑制生物膜形成	[35]
RN3（5-17P22-36）	成熟阶段	铜绿假单胞菌	人源衍生物	清除成熟生物膜;杀灭生物膜细菌	[10]
PEP-NJSM	黏附阶段形成阶段成熟阶段	表皮葡萄球菌	人病毒蛋白组	减少原始细菌黏附;抑制生物膜细菌活性;提高生物膜细菌死亡率	[43]
IDR-1018	形成阶段成熟阶段	粪肠球菌金黄色葡萄球菌铜绿假单胞菌鲍曼不动杆菌	牛	清除成熟生物膜;提高抗生素或者抗微生物肽的抗生物膜能力	[44]
BMAP-28	黏附阶段	白色念珠菌	牛	杀灭浮游细菌	[25]
CRAMP	成熟阶段	铜绿假单胞菌	鼠	清除成熟生物膜	[21]
P318	形成阶段	白色念珠菌大肠杆菌铜绿假单胞菌	鼠源衍生物	抑制生物膜细菌活性	[20]
Cath-2	黏附阶段成熟阶段	表皮葡萄球菌	鸡	减少原始细菌黏附;杀灭生物膜细菌	[45]
MC1	形成阶段	铜绿假单胞菌	蛙源衍生物	下调Pel、AlgD和Psl基因抑制多糖合成	[26]
PT13	形成阶段	金黄色葡萄球菌	胡杨	抑制细胞粘附和粘附蛋白编码基因表达	[7]
CLP	形成阶段成熟阶段	表皮葡萄球菌	淀粉芽孢杆菌	降低EPS组分（多糖、蛋白质、eDNA）;破坏EPS结构	[5]
Nisin	形成阶段	铜绿假单胞菌	乳酸链球菌	降低生物膜多糖、eDNA含量;减少原始细菌黏附	[15]
Pep19-2.5	形成阶段	变异链球菌	人工合成	抑制细菌生长活性	[46]
P5	形成阶段	铜绿假单胞菌	人工合成	破坏生物膜结构;杀灭生物膜细菌	[42]
ZY4	成熟阶段	铜绿假单胞菌	人工合成	清除成熟生物膜和杀灭持留菌	[22]
KP	形成阶段成熟阶段	白色念珠菌	人工合成	破坏生物膜结构;抑制生物膜形成相关基因表达	[23]
LIVRHK;LIVRRK	形成阶段	铜绿假单胞菌	人工合成	抑制了Lasl/R和Rhl/R的表达;抑制毒力因子产生	[28]
WLBU2	形成阶段	铜绿假单胞菌	人工合成	抑制生物膜形成	[41]