【摘要】：結(jié)核病是由結(jié)核分枝桿菌引起的一種世界性傳染病,近年來隨著人口流動增加、HIV與結(jié)核分枝桿菌伴發(fā)感染以及結(jié)核分枝桿菌多重耐藥性菌株的出現(xiàn)等原因,使全球結(jié)核病疫情再度回升,其中耐藥菌株的出現(xiàn)是治療失敗的主要原因。結(jié)核分枝桿菌由于其特殊的細胞壁結(jié)構(gòu),對多種藥物有天然的耐藥性,耐藥機制復(fù)雜。1998年,Cole等發(fā)布了結(jié)核分枝桿菌H37Rv全基因測序結(jié)果,使人們能從基因水平研究結(jié)核分枝桿菌的耐藥機制。 隨著耐多藥結(jié)核分枝桿菌感染的出現(xiàn),人們期待更加有效的藥物出現(xiàn),從而把更多的目光投向了二線藥物,其中喹諾酮類藥物尤其受到青睞。喹諾酮類藥物為一類全合成的抗菌制劑,自1962年發(fā)現(xiàn)了奈啶酸(Nalidixic acid)以來,已有四代喹諾酮類藥物上市,但只有第三代的喹諾酮類抗菌藥具有抗分枝桿菌活性。喹諾酮類藥物主要作用于結(jié)核桿菌DNA促旋酶,該酶由A、B亞單位組成,藥物的耐藥性主要由于作用靶位的改變,A亞單位突變常常導(dǎo)致高耐藥,B亞單位突變常常導(dǎo)致低耐藥,而有的低水平的耐藥常常缺乏喹諾酮類藥物靶位的改變,有時高水平的耐藥又不能單一地用靶位的改變來解釋,所以還有其他的耐藥機制的存在。隨著喹諾酮類藥物的廣泛使用,耐藥菌株也日漸顯現(xiàn),嚴重影響其療效和臨床應(yīng)用。研究喹諾酮耐藥產(chǎn)生機制,就具有重要意義。 本研究利用生物信息學的方法對結(jié)核分枝桿菌全基因組進行分析發(fā)現(xiàn),結(jié)核分枝桿菌基因組中大約有20種外排蛋白編碼基因,其中多數(shù)與
[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
【學位授予單位】：四川大學
【學位級別】：博士
【學位授予年份】：2005
【分類號】：R378

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