NDM-4和NDM-5型金属β-内酰胺酶在肠杆菌科细菌中传播流行的分子机制

发布时间：2018-01-13 12:30

本文关键词：NDM-4和NDM-5型金属β-内酰胺酶在肠杆菌科细菌中传播流行的分子机制　出处：《郑州大学》2017年硕士论文　论文类型：学位论文

【摘要】：碳青霉烯耐药肠杆菌科细菌(Carbapenem-resistant Enterobacteriaceae,CRE)近年来在国内的分离率呈逐渐上升的趋势。CRE多重耐药情况严重,治疗用药选择有限,患者被感染后死亡率高,给临床抗感染治疗带来极大挑战。美国疾病控制与预防中心发布《美国2013年抗生素耐药性威胁》报告,将CRE列为最高“紧急”威胁级别。NDM型金属β-内酰胺酶(New Delhi metallo-β-lactamase,NDM)能够水解除单环β-内酰胺类之外所有β-内酰胺类抗生素,是介导CRE产生的主要因素之一。截止目前,已有17种不同的NDM酶亚型在全球不同国家和地区被报道,这些亚型(除NDM-11和NDM-15外)与NDM-1相比,由于个别碱基的差异导致氨基酸序列发生变化,进而改变酶对β-内酰胺类抗生素的水解活力。本课题组前期研究发现NDM-1酶在河南地区分离的CRE中出现高发流行,随后又连续跟踪了CRE在我省的流行,进一步探讨NDM不同亚型在河南省的流行情况。本课题依托河南省耐药监测网连续三年对金属β-内酰胺酶在河南地区的传播流行进行跟踪,发现NDM-1的流行发生了变化,2014年发现1株产NDM-4的大肠杆菌,这是国内首次发现NDM-4亚型;2014和2015年共发现23株产NDM-5的CRE。针对以上CRE的耐药机制展开深入研究发现:1、携带NDM-4的ST410型大肠杆菌耐药谱广,除携带bla_(NDM-4)基因外,还携带其他耐药基因,bla_(NDM-4)基因位于约54 kb的IncX3型质粒上。2、分子流行病学研究表明NDM-5亚型已开始在我省分离的CRE中出现流行,且产NDM-5酶的CRE同源性较低,遗传具有多样性,优势克隆ST167型大肠杆菌有可能成为区域性流行克隆;对NDM-5的质粒进行分析,结果显示,携带bla_(NDM-5)基因的质粒大小均约为45 kb,表明有可能是同一质粒的水平传播导致bla_(NDM-5)基因的播散。通过本课题的研究,初步揭示了我省肠杆菌科细菌中NDM-4、NDM-5酶亚型传播、流行的分子特征,为防控bla_(NDM-4)、bla_(NDM-5)基因的进一步播散提供数据支持,也为临床治疗NDM耐药菌引起的重症感染提供理论依据。
[Abstract]:Carbapenem-resistant Enterobacteriaceae. In recent years, the separation rate of CRE in China is increasing gradually. The situation of CRE multidrug resistance is serious, the choice of treatment drug is limited, and the mortality rate of patients after infection is high. The U. S. Centers for Disease Control and Prevention released the 2013 threat of antibiotic Resistance in the United States. CRE was classified as the highest "emergency" threat level. New Delhi metallo- 尾 -lactamase was classified as metallo- 尾 -lactamase. NDMs can release all 尾-lactams except monocyclic 尾-lactams, which is one of the main factors that mediate the production of CRE. Seventeen different NDM subtypes have been reported in different countries and regions of the world. These subtypes (except NDM-11 and NDM-15) are compared with NDM-1. The amino acid sequence changes due to the difference of individual bases. Then the hydrolysis activity of 尾-lactam antibiotics was changed. Our previous study found that NDM-1 enzyme was highly prevalent in CRE isolated from Henan province. And then followed up on the popularity of CRE in our province. To further investigate the prevalence of different subtypes of NDM in Henan Province, this study tracked the spread and prevalence of metal 尾 -lactamases in Henan for three consecutive years, based on the drug resistance monitoring network of Henan Province. It was found that the prevalence of NDM-1 had changed. In 2014, a strain of E. coli producing NDM-4 was found. This is the first time that NDM-4 subtype has been found in China. A total of 23 NDM-5 producing strains were found in 2014 and 2015. A further study on the drug resistance mechanism of the above CRE was carried out and found that: 1. NDM-4 carrying ST410 Escherichia coli has a wide spectrum of drug resistance, in addition to carrying blahs NDM-4 gene, but also other drug-resistant genes. The NDM-4) gene is located on about 54 kb of IncX3 type plasmid. Molecular epidemiology studies show that NDM-5 subtype has begun to be prevalent in CRE isolated in our province. The homology of CRE producing NDM-5 enzyme was low and the genetic diversity was high. The dominant clone of ST167 type Escherichia coli might become a regional epidemic clone. The plasmids of NDM-5 were analyzed. The results showed that the plasmids carrying the blast/ NDM-5 gene were about 45kb in size. It is suggested that the horizontal transmission of the same plasmid may lead to the spread of NDM-5) gene. The NDM-4 in Enterobacteriaceae in our province was preliminarily revealed by the research in this paper. The transmission of NDM-5 subtype, the molecular characteristics of epidemic, provides data support for the further dissemination of NDM-4 / NDM-5) gene. It also provides a theoretical basis for the clinical treatment of severe infection caused by NDM resistant bacteria.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R446.5

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