抗菌肽NZ2114对多重耐药2型猪链球菌感染小鼠的治疗效果评价

doi:10.16431/j.cnki.1671-7236.2018.04.032

《中国畜牧兽医》 ›› 2018, Vol. 45 ›› Issue (4): 1089-1097.doi: 10.16431/j.cnki.1671-7236.2018.04.032

抗菌肽NZ2114对多重耐药2型猪链球菌感染小鼠的治疗效果评价

赵飞^1,2,3,4, 滕达^3,4, 杨娜^3,4, 王秀敏^3,4, 毛若雨^3,4, 郝娅^3,4, 李占占^3,4, 王潇^3,4, 范寰², 王建华^3,4

1. 天津师范大学生命科学学院, 天津 300387;
2. 天津市畜牧兽医研究所, 天津 300381;
3. 农业部饲料生物技术重点实验室, 北京 100081;
4. 中国农业科学院饲料研究所基因工程研究室, 北京 100081

修回日期:2018-02-11 出版日期:2018-04-20 发布日期:2018-04-25
通讯作者: 范寰(1971-),女,天津人,副研究员,研究方向:饲料微生物,E-mail:fanhuan13212107231@126.com;王建华(1961-),男,湖北仙桃人,研究员,研究方向:抗菌肽及抗生素替代品,E-mail:wangjianhua@caas.cn E-mail:fanhuan13212107231@126.com;wangjianhua@caas.cn
作者简介:赵飞(1990-),女,山西太原人,硕士生,研究方向:抗菌肽及抗生素替代品,E-mail:2293116769@qq.com
基金资助:
国家农业科技创新工程——抗菌肽及抗生素替代品方向（CAAS-ASTIP-2013-FRI-02，2013-2017）

Evaluation of the Therapeutic Efficacy of Antimicrobacterial Peptide NZ2114 in Mice Infected with Streptococcus suis Serotype 2

ZHAO Fei^1,2,3,4, TENG Da^3,4, YANG Na^3,4, WANG Xiumin^3,4, MAO Ruoyu^3,4, HAO Ya^3,4, LI Zhanzhan^3,4, WANG Xiao^3,4, FAN Huan², WANG Jianhua^3,4

1. College of Life Sciences, Tianjin Normal University, Tianjin 300387, China;
2. Tianjin Animal Science and Veterinary Research Institute, Tianjin 300381, China;
3. Key Laboratory of Feed Biotechnology, Ministry of Agriculture, Beijing 100081, China;
4. Gene Engineering Laboratory, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China

Revised:2018-02-11 Online:2018-04-20 Published:2018-04-25

摘要/Abstract

摘要：

为探究抗菌肽NZ2114对猪链球菌感染小鼠模型的体内治疗效果，本试验以NZ2114和2型猪链球菌CVCC 3928为研究对象，利用小鼠模型评价NZ2114治疗猪链球菌感染的效果。36只ICR雌鼠随机均分为6组：空白对照组（不感染，腹腔注射0.2 mL PBS）、阴性对照组（感染，腹腔注射0.2 mL PBS）、试验Ⅰ和Ⅱ组（感染，分别腹腔注射0.2 mL 2.5和5.0 mg/kg NZ2114）、阳性对照Ⅰ和Ⅱ组（感染，分别腹腔注射0.2 mL 7.5和15.0 mg/kg头孢曲松钠）。结果显示，空白对照组和5.0 mg/kg NZ2114试验组小鼠存活率均为100%，而15.0 mg/kg头孢曲松钠阳性对照组小鼠存活率仅为50%。治疗1 d后，5.0 mg/kg NZ2114试验组小鼠肺脏和肝脏荷菌量分别下降59.41%（P < 0.01）和69.19%（P < 0.01）；而15.0 mg/kg头孢曲松钠阳性对照组中小鼠肺脏和肝脏荷菌量分别下降43.94%（P < 0.01）和19.60%（P < 0.05）。与阴性对照组相比，2.5 mg/kg NZ2114治疗组中抑制炎性因子TNF-α和IL-1β的释放分别下降85.83%（P < 0.01）和56.20%（P < 0.05），5.0 mg/kgNZ2114试验组分别降低84.02%（P < 0.01）和43.86%（P < 0.05），而15.0 mg/kg头孢曲松钠阳性对照组TNF-α及IL-1β的下降率均不显著，分别为24.49%和8.82%。另外，5.0 mg/kg NZ2114试验组1 d后即可明显减轻小鼠肺组织间质弥漫性炎细胞浸润等炎症症状，抑制肝细胞产生肿胀及空泡性变化，促进脾小结恢复正常；治疗7 d后各器官组织临床症状评分基本恢复正常。上述结果表明，NZ2114能有效提高猪链球菌感染小鼠的存活率，显著降低病原菌在小鼠肺脏和肝脏的移位及血清中TNF-α和IL-1β的水平，并有效缓解肝脏、脾脏和肺脏的急性损伤，治疗效果优于头孢曲松钠，具有作为治疗临床猪链球菌病抗生素替代品的潜力。

关键词: 抗菌肽NZ2114; 2型猪链球菌; 小鼠; 存活率; 脏器荷菌量; 炎性因子

Abstract:

In order to explore in vivo therapeutic efficacy of antimicrobial peptide NZ2114 against Streptococcus suis (S.suis),the evaluation was performed on the mice model,in which NZ2114 and S.suis serotype 2 CVCC 3928 were used as objects of this study.36 female ICR mice were randomly divided into 6 groups:Blank control group (no infection,intraperitoneal injection of 0.2 mL PBS),negative control group (infection,intraperitoneal injection of 0.2 mL PBS),test groups Ⅰ and Ⅱ (infection,intraperitoneal injection of 0.2 mL 2.5 and 5.0 mg/kg NZ2114,respectively),positive control groups Ⅰ and Ⅱ (infection,intraperitoneal injection of 0.2 mL 7.5 and 15.0 mg/kg ceftriaxone sodium,respectively).The results showed that the survival rates of blank control group and 5.0 mg/kg NZ2114 test group were both 100%,while that of 15.0 mg/kg ceftriaxone sodium positive control group was only 50%.The bacteria load in liver and lung decreased 59.41% (P < 0.01) and 69.19% (P < 0.01) in 5.0 mg/kg NZ2114 test group,and those of 15.0 mg/kg ceftriaxone sodium positive control group decreased 43.94% (P < 0.01) and 19.60% (P < 0.05),respectively.Compared with negative control group,the levels of TNF-α and IL-1β in mice serum decreased 85.83% (P < 0.01) and 56.20% (P < 0.05) in 2.5 mg/kg NZ2114 test group,those of 5.0 mg/kg NZ2114 test group decreased 84.02% (P < 0.01) and 43.86% (P < 0.05),and those of 15.0 mg/kg ceftriaxone sodium positive control group decreased 24.49% and 8.82%,respectively.Moreover,after treatment of 5.0 mg/kg NZ2114 for 1 d,the diffuse interstitial infiltration of inflammatory cells and other inflammatory symptoms in lung tissue obviously reduced,swelling and vacuoles changes produced by liver cells were inhibited and splenic nodules returned to normal,and the basic clinical symptoms were recovered to normal after treatment for 7 d.These results suggested that NZ2114 could effectively increase the survival rate of mice,decrease the bacterial translocation in lung and liver,inhibit the release of TNF-α and IL-1β,and relieve the lung,liver and spleen from acute injury induced by S. suis,which were better than ceftriaxone sodium and indicated that NZ2114 had a good potential as an antibiotic substitute for the treatment of S. suis serotype 2 disease.

Key words: antimicrobial peptide NZ2114; Streptococcus suis serotype 2; mice; survival rate; bacteria load in organ; inflammatory factor

中图分类号:

S816.7

赵飞, 滕达, 杨娜, 王秀敏, 毛若雨, 郝娅, 李占占, 王潇, 范寰, 王建华. 抗菌肽NZ2114对多重耐药2型猪链球菌感染小鼠的治疗效果评价[J]. 《中国畜牧兽医》, 2018, 45(4): 1089-1097.

ZHAO Fei, TENG Da, YANG Na, WANG Xiumin, MAO Ruoyu, HAO Ya, LI Zhanzhan, WANG Xiao, FAN Huan, WANG Jianhua. Evaluation of the Therapeutic Efficacy of Antimicrobacterial Peptide NZ2114 in Mice Infected with Streptococcus suis Serotype 2[J]. , 2018, 45(4): 1089-1097.

参考文献

[1] 祝令伟,纪雪,李丽红,等.屠宰场猪链球菌分离菌株分型及其致病性和耐药性分析[J].中国兽医学报,2017,37(2):272-277. ZHU L W,JI X,LI L H,et al.Molecular characterization,pathogenicity and drug-resistance of Streptococcus suis isolated from slaughterhouse pigs[J].Chinese Journal of Veterinary Science,2017,37(2):272-277.(in Chinese)
[2] LUN Z R,WANG Q P,CHEN X G,et al.Streptococcus suis:An emerging zoonotic pathogen[J].Lancet Infectious Diseases,2007,7(3):201-209.
[3] GROVES M D,JORDAN D,CHAPMAN T A,et al.Multilocus sequence typing of Australian Streptococcus suis,type 2 by MALDI-TOF mass spectrometry analysis of PCR amplicons[J].Veterinary Microbiology,2015,177(3-4):394-397.
[4] VARELA N P,GADBOIS P,THIBAULT C,et al.Antimicrobial resistance and prudent drug use for Streptococcus suis[J].Animal Health Research Reviews,2013,14(1):68-77.
[5] FENG Y,ZHANG H,WU Z,et al.Streptococcus suis infection:An emerging/reemerging challenge of bacterial infectious diseases?[J].Virulence,2014,5(4):477-497.
[6] CALLENS B F,HAESEBROUCK F,MAES D,et al.Clinical resistance and decreased susceptibility inStreptococcus suis isolates from clinically healthy fattening pigs[J].Microbial Drug Resistance,2013,19(2):146-151.
[7] FENG Y,ZHANG H,MA Y,et al.Uncovering newly emerging variants of Streptococcus suis,an important zoonotic agent[J].Trends in Microbiology,2010,18(3):124-131.
[8] WANG X M,TENG D,MAO R Y,et al.Combined systems approaches reveal a multistage mode of action of a marine antimicrobial peptide against pathogenic Escherichia coli and its protective effect against bacterial peritonitis and endotoxemia[J]. Antimicrobial Agents and Chemotherapy,2016,61(1):e01056-16.
[9] ZHANG Y,TENG D,MAO R,et al.High expression of a plectasin-derived peptide NZ2114 in Pichia pastoris and its pharmacodynamics,postantibiotic and synergy against Staphylococcus aureus[J].Applied Microbiology and Biotechnology,2014,98(2):681-694.
[10] ANDES D,CRAIG W,NIELSEN L A,et al.In vivo pharmacodynamic characterization of a novel plectasin antibiotic,NZ2114,in a murine infection model[J].Antimicrobial Agents and Chemotherapy,2009,53(7):3003-3009.
[11] BRINCH K S,TULKENS P M,VAN BAMBEKE F,et al.Intracellular activity of the peptide antibiotic NZ2114:Studies with Staphylococcus aureus and human THP-1 monocytes,and comparison with daptomycin and vancomycin[J].Journal of Antimicrobial Chemotherapy,2010,65(8):1720-1724.
[12] JIAO J,MAO R Y,TENG D,et al.In vitro and in vivo antibacterial effect of NZ2114 against Streptococcus suis type 2 infection in mice peritonitis models[J].Applied Microbiology and Biotechnology Express,2017,7(1):44.
[13] ROTTA A T,GUNNARSSON B,HERNAN L J,et al.Partial liquid ventilation influences pulmonary histopathology in an animal model of acute lung injury[J].Journal of Critical Care,1999,14(2):84-92.
[14] KNODELL M D,ISHAK K G,BLACK W C,et al.Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis[J].Hepatology,1981,1(5):431-435.
[15] LEBEL G,PICHE F,FRENETTE M,et al.Antimicrobial activity of nisin against the swine pathogen Streptococcus suis and its synergistic interaction with antibiotics[J].Peptides,2013,50(3):19-23.
[16] 张玉玉,王可,黄保华,等.柞蚕抗菌肽Moricin的抑菌活性研究[J].山东农业科学,2016,48(1):119-122. ZHANG Y Y,WANG K,HUANG B H,et al.Research on antibacterial activity of antibacterial peptide Moricin from Antherea pernyi[J].Shandong Agricultural Sciences,2016,48(1):119-122.(in Chinese)
[17] RAMESH G,REEVES W B.TNF-α mediates chemokine and cytokine expression and renal injury incisplatin nephrotoxicity[J].Journal of Clinical Investigation,2002,110(6):835-842.
[18] DINARELLO C A,OKUSAWA S,GELFAND J A.Interleukin-1 induces a shock-like state in rabbits:Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition[J].Progress in Clinical and Biological Research,1988,81(4):1162-1172.
[19] LIN X,FENG H Q,PANG X Y,et al.Mesosome formation is accompanied by hydrogen peroxide accumulation in bacteria during the rifampicin effect[J].Molecular and Cellular Biochemistry,2008,311(1-2):241-247.
[20] SARAIVA M,O'GARRA A.The regulation of IL-10 production by immune cells[J].Nature Reviews Immunology,2010,10(3):170-181.
[21] PATEL J.IL-10 reprogramming of metabolism in macrophages throughmitophagy[J].Cardiovascular Research,2017,113(11):e40-e41.
[22] 马沛,蒋秋云,陈小军,等.头孢噻呋混悬剂对猪链球菌Ⅱ型小鼠模型的治疗试验[J].中国畜牧兽医,2010,37(5):175-177. MA P,JIANG Q Y,CHEN X J,et al.Efficacy of ceftiofur suspension experimentally induced with Streptococcus suis serotype Ⅱ in mice[J].China Animal Husbandry & Veterinary Medicine,2010,37(5):175-177.(in Chinese)
[23] 周光炎.免疫学原理[M].北京:科学技术文献出版社,2017. ZHOU G Y.The Principle of Immunology[M].Beijing:Science and Technology Literature Press,2017.

抗菌肽NZ2114对多重耐药2型猪链球菌感染小鼠的治疗效果评价

Evaluation of the Therapeutic Efficacy of Antimicrobacterial Peptide NZ2114 in Mice Infected with Streptococcus suis Serotype 2

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