结核分枝杆菌喹诺酮耐药基因功能研究

发布时间：2018-07-31 12:32

【摘要】：结核病是由结核分枝杆菌引起的一种世界性传染病,近年来随着人口流动增加、HIV与结核分枝杆菌伴发感染以及结核分枝杆菌多重耐药性菌株的出现等原因,使全球结核病疫情再度回升,其中耐药菌株的出现是治疗失败的主要原因。结核分枝杆菌由于其特殊的细胞壁结构,对多种药物有天然的耐药性,耐药机制复杂。1998年,Cole等发布了结核分枝杆菌H37Rv全基因测序结果,使人们能从基因水平研究结核分枝杆菌的耐药机制。随着耐多药结核分枝杆菌感染的出现,人们期待更加有效的药物出现,从而把更多的目光投向了二线药物,其中喹诺酮类药物尤其受到青睐。喹诺酮类药物为一类全合成的抗菌制剂,自1962年发现了奈啶酸(Nalidixic acid)以来,已有四代喹诺酮类药物上市,但只有第三代的喹诺酮类抗菌药具有抗分枝杆菌活性。喹诺酮类药物主要作用于结核杆菌DNA促旋酶,该酶由A、B亚单位组成,药物的耐药性主要由于作用靶位的改变,A亚单位突变常常导致高耐药,B亚单位突变常常导致低耐药,而有的低水平的耐药常常缺乏喹诺酮类药物靶位的改变,有时高水平的耐药又不能单一地用靶位的改变来解释,所以还有其他的耐药机制的存在。随着喹诺酮类药物的广泛使用,耐药菌株也日渐显现,严重影响其疗效和临床应用。研究喹诺酮耐药产生机制,就具有重要意义。本研究利用生物信息学的方法对结核分枝杆菌全基因组进行分析发现,结核分枝杆菌基因组中大约有20种外排蛋白编码基因,其中多数与
[Abstract]:Tuberculosis is a worldwide infectious disease caused by Mycobacterium tuberculosis. In recent years, with the increase of population flow, HIV co-infection with Mycobacterium tuberculosis and the emergence of multidrug resistant strains of Mycobacterium tuberculosis, etc. The emergence of resistant strains is the main reason for the failure of treatment. Because of its special cell wall structure, Mycobacterium tuberculosis has natural drug resistance and complex drug resistance mechanism. In 1998, H37Rv gene sequencing of Mycobacterium tuberculosis was published by Cole et al. It is possible to study the drug resistance mechanism of Mycobacterium tuberculosis at the gene level. With the emergence of multi-drug-resistant Mycobacterium tuberculosis infection, more effective drugs are expected, and more attention is paid to second-line drugs, especially quinolones. Quinolones are a class of total synthetic antimicrobial agents. Since the discovery of (Nalidixic acid) in 1962, there have been four generations of quinolones on the market, but only the third generation quinolones have antimicrobial activity against Mycobacterium. Quinolones mainly act on Mycobacterium tuberculosis DNA prospirase, which is composed of DNA B subunits. The drug resistance of quinolones is mainly due to the change of target sites, which often leads to high drug resistance subunit B mutation and low drug resistance. Some low levels of drug resistance often lack of changes in quinolones, and sometimes high levels of drug resistance can not be explained by the change of target, so there are other mechanisms of drug resistance. With the widespread use of quinolones, drug-resistant strains are becoming increasingly apparent, seriously affecting its efficacy and clinical application. It is of great significance to study the mechanism of quinolone resistance. In this study, bioinformatics was used to analyze the whole genome of Mycobacterium tuberculosis. It was found that there are about 20 excipient protein coding genes in the genome of Mycobacterium tuberculosis, most of which are associated with
【学位授予单位】：四川大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R378

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