重庆市结核病耐药的流行病学调查及耐药相关基因分子特征研究
|
摘要
耐药结核病尤其耐多药结核病(Multi-drug resistance tuberculosis,MDR-TB)的发生和流行是自20世纪80年代中后期以来结核病疫情回升的主要原因之一。预防和控制耐(多)药结核病已经成为当前结核病控制的主要任务,而了解结核病耐药疫情基线数据和流行病学特征是制定预防和控制耐药结核病的重要依据。世界卫生组织和国际防痨和肺病联合会(WH0/IUATLD)为了解全球耐药结核病总的分布情况,于1994年启动全球结核病耐药性监测计划,在1994~2002年间,对全球114个国家和地区进行了抗结核一线药物(链霉素、异烟肼、利福平、乙胺丁醇)的耐药性的调查,覆盖全球约50%的人口,其调查结果显示全球耐(多)药结核病呈不断蔓延扩散的趋势,发展中国家和地区上升尤为显著。我国属于耐药程度较高的国家之一,被WHO列为“特别引起警示的国家和地区”和MDR-TB的“热点”地区之一。
流行病学调查显示:通常经济和卫生、医疗条件等较差的地区,耐药结核病疫情尤为严重,同时结核病疫情和耐药结核病的流行病学特征存在明显的地区差异。重庆地处西南,农村人口多,经济不够发达,近10年尚无大样本量的耐(多)药结核病相关流行病学研究调查报道,因此了解本市耐(多)药结核病的相关基线资料和流行病学特征对于促进耐(多)药结核病的控制有重要意义。本研究第一部分,即是对在2003年~2006年在重庆市法定结核病防治机构(结核病防治所和胸科医院)连续收集的痰培养阳性的1089例结核病病例的耐药情况和流行病学特征进行分析。
异烟肼(Isoniazide,INH)和乙胺丁醇(ethambutol,EMB)是WHO推荐使用的一线抗结核组合药物之一。近年WHO/IUATLD在全球的结核病耐药监测结果显示:全球INH平均耐药率为5.6%,大多数国家和地区INH耐药率呈现逐年上升趋势,且在四种一线抗结核药物(INH,RFP,SM和EMB)中,INH耐药率在各国和地区均排列第一或第二位,我国INH耐药率为17.6%,耐药水平较高。全球平均EMB耐药率为0.8%(0~24.8),尽管总体耐药水平较低,但呈逐年快速上升趋势,我国EMB耐药率(1.5%)显著高于全球平均EMB耐药水平。INH和EMB耐药率的高企和升高,将明显影响WHO推荐的以此为主要组合药物方案治疗结核病的疗效。从降低耐药结核病病人死亡、减少传染源、缩短传染期的角度来看,早期诊断、早期选择敏感药物治疗耐药结核病病例是预防和控制耐(多)药结核病和减少卫生资源浪费的重要措施之一。但目前以培养为基础的药敏检测方法需要较长的时间(1~3月)才能得到结果,难以实现早期诊断和及时指导临床用药的目的。随着分子生物学理论和技术的发展,结核分枝杆菌INH耐药和EMB耐药的分子机制得到一定程度的阐明,目前研究已经证实结核分枝杆菌内编码活化INH所必需的过氧化氢酶-过氧化物的katG基因(尤其katG315)的变异是INH耐药性产生的最主要分子机制,但katG315在不同地区的INH耐药结核分枝杆菌中的变异率存在明显差异,从26%至95%不等。结核分枝杆菌中编码阿拉伯糖基转移酶的embB基因突变(尤其306位密码子)是引起结核分枝杆菌乙胺丁醇耐药的最主要原因, embB306突变覆盖约50%~70%的EMB耐药菌株,是目前与EMB耐药最相关的分子生物学标记物。部分地区已将katG315和embB306突变作为耐药分子标记物,采用PCR-FRLP和PCR-SSCP等方法进行临床INH和EMB耐药菌株的检测,实现了INH和EMB耐药病例的早期诊断和及时指导临床治疗,具有较高的特异性和敏感性,研究证明katG315、embB306分别在INH、EMB耐药结核杆菌中突变率较高的地区,这些快速、价廉的分子生物学方法在临床上应用是可行的。由于分子生物学检测方法是通过基因型来推测细菌耐药的表型,且katG基因和embB基因变异具有明显的地域分布特点,重庆地区尚无这两个基因在结核分枝杆菌中的突变谱、突变率的研究报道,katG315和embB306是否是本地区INH耐药、EMB耐药结核分枝杆菌的主要分子机制?是否可分别用于筛选或检测INH耐药、EMB耐药结核病的分子标记物?有待研究阐明。本研究第二部分和第三部分采用测序方法分别对重庆不同耐药组合的97株结核分枝杆菌中的katG基因和101株结核分枝杆菌中的embB基因的多态性及它们与耐药相关性进行了分析,将有助于阐明以上问题。主要结果和结论如下:
一、第一部分重庆市2003 ~2006年结核病耐药情况的流行病学调查
1.重庆市结核病总耐药率和耐多药率分别是27.6%(301/1089)和7.3%(79/1089);其中初治耐药率和耐多药率分别是22.7%、4.1%,复治耐药率和耐多药率分别是56.2%、26.5%。整体耐药水平与国内外监测结果比较,处于中等水平。
2. SM、INH、RFP、EMB耐药率分别是16.3%、14.0%、10.7%和4.7%;近3年RFP、EMB耐药率和耐多药率呈逐年上升趋势。
3.耐(多)药病例分布无明显性别和年龄特征,但与用药史、经济条件差(居住乡村、可支配年收入低于平均水平)存在较强联系。提示耐(多)药结核病防治应重点加强直接面视下督导短程化疗( Directly Observed Treatment Short course, DOTS)方案的实施和经济条件较差的结核病病例的规律全程治疗。
4.耐药病例的分布特征提示:重庆地区可能存在一定范围、一定程度的耐药结核分枝杆菌的传播,应加强结核病的耐药监测尤其分子水平的监测,有利于早期发现和预防耐药结核分枝杆菌大规模的扩散,对于控制耐(多)药结核病疫情有重要意义。
二、第二部分重庆市97株结核分枝杆菌的katG315突变特征及其与异烟肼耐药相关性的研究
1.重庆地区INH耐药结核分枝杆菌中katG315突变谱包括S315T、S315N和S315三种类型,总突变率为75.5%(37/49),其中81.1%(30/37)为S315T突变型,INH敏感菌株中未见katG315突变。katG315突变是本地区结核分枝杆菌INH耐药的主要分子机制。
2.以katG315突变做为诊断INH耐药菌株的标记物,与传统药敏试验比较,灵敏度为75.5%,特异度为100%,准确度为87.6%(85/97),其他各项评价指标均提示:在本地区,该指标用于INH耐药菌株的快速诊断具有较好的的临床应用价值。
3. katG315在高度耐药(1ug/ml)和耐多药菌株中的突变率分布分别显著高于低度耐药(0.2 ug/ml)和单耐INH菌株,且与耐药数量有关,一定程度上表明katG315突变与耐药程度有关。
4. katG突变率分析显示:katG315变异是本地区INH耐药产生的主要分子机制,24.5%的INH耐药株未见katG315变异,表明在本地区还存在其他INH耐药的分子机制,对于本地区结核病、耐药结核病的防治有一定参考价值。
三、第三部分重庆101株结核分枝杆菌的embB306突变特征及其与乙胺丁醇耐药相关性的研究
1. embB306在EMB耐药菌株中突变率有明显地域差异,重庆地区EMB耐药菌株中embB306突变率66.7%,34/51显著高于EMB敏感菌株的突变率(6.0%,3/50)(P〈0.01),与传统药敏实验比较,embB306突变作为EMB耐药标记物检测EMB耐药的灵敏度为66.7%(34/51),特异度为90%(45/50),准确度为78.2%(79/101)。提示在没有更好标记物情况下,embB306突变应用于本地区的EMB耐药菌株的检测有一定临床意义。
2. embB306在EMB耐药MDR菌株中突变率为84.0%(21/25)显著高于非MDR菌株中的突变率(50.0%,13/26),且突变率随耐药数量增加而增加,提示embB306突变与耐药程度有关。
3. embB突变谱较广泛,embB306突变覆盖66.7%(34/51)的EMB耐药菌株,提示embB306突变是本地区EMB耐药产生的主要分子机制,其他分子机制可能与大量稀少突变及其联合作用有关。
总之,通过本研究获得了重庆结核病耐药基线资料和耐药结核病的主要流行病学特征;同时明确了KatG315和embB306突变分别是本地区结核分枝杆菌INH、EMB耐药的主要分子机制,它们作为INH、EMB耐药快速检测的分子标记物具有一定临床应用价值。该研究结果对于本地区结核病、耐药结核病的防治有一定参考价值。
The incidence and infection of drug resistance tuberculosis (DR-TB), especially for the multi-drug resistance tuberculosis (MDR-TB) is one of the major cause to revive the epidemic of tuberculosis. WHO and IUATLD launched a global program for surveillance of drug resistance in 1994 to identify global DR-TB distribution, and conducted a resistance investigation on the first line drugs, including streptomycin(SM), isoniazid(INH) rifampicin (RFP) and ethambutol(EMB), among114 countries and area in the world from 1994 to 2003 to disclose the growing tendency of MDR-TB in developing countries. China is on the list of“Countries and Districts need more attention”proposed by WHO due to the severe situation of drug resistance. MDR-TB problem in China is also a“hot topic”.
The main task for TB control at present is to prevent and control MDT-TB, for which, the baseline information and epidemic characteristics of DT-TB shall be collected for reference to make preventive or administrative policies. However, both DR-TB information and epidemic characteristics show regional differences. Located in southwest, Chongqing is confronted with the pressure of large rural population and relatively underdeveloped economy. In the last decade, there is no local report on (M)DR-TB based on large sample size. In a word, the baseline information and epidemic characteristics of local (M)DR-TB is critical to DR-TB control. Section 1 in the present study disclosed smear positive samples sequentially collected by authorized local TB prevention organization (Tuberculosis Prevention and Control Institute, chest hospital etc.), total 1089 cases, and the analysis of drug resistant information and epidemic characteristics thereof.
INH and EMB are the first line TB resistance drugs recommended by WHO and one of the indispensable compound drugs for TB treatment. According to the global surveillance report on drug resistance tuberculosis by WHO, the resistance rate of INH is rising yearly around the world. Of all the four TB drugs (INH, RFP, SM and EMB), the resistance rate of INH is the highest or the second highest, 5.6% on average. China’s INH resistance rate is 17.6%, rather a high level. Generally speaking, the global EMB resistance rate is low, only 0.8% (0~24.8) on average, but rising rapidly every year. China’s EMB resistance rate (1.5%) is higher than the global average value.
To reduce death rate of DR-TB patients, infection sources and infection period, diagnosis and selection of sensitive drugs at the early stage is the most important method to help TB patients. However, the present drug sensitivity testing method based on culture is too time-consuming (1-3months) to be used in clinic timely. The developing molecular biological theories and techniques shed some light on the molecular mechanism of INH resistance and EMB resistance of mycobacterium tuberculosis. Up to now, researchers have proved that the mutation katG genes (especially katG315), an indispensible catalase- peroxide to INH activation by internal-coding of mycobacterium tuberculosis, is the major cause for INH resistance. Also the mutation rates of katG315 in INH-resistant mycobacterium tuberculosis shows regional differences (26%~95%). The mutation of embB (especially the 306th codon), the gene that is responsible for coding arabinose glycosyltransferase is the major cause to lead EMB resistance. embB 306 mutation was detected on 50%~70% EMB-resistant stains, so it is regarded as the molecular biological marker closely related to EMB resistance. katG315 mutation and embB306 mutation are used as the clinic testing methods for INH and EMB resistance respectively in some regions, by which the diagnosis and therapy of INF or EMB resistance are realized as well as showing high sensitivity and specificity. So it is safe to declare the feasibility of applying those rapid and economical molecular biological methods to clinic.
Molecular biology is to estimate the phenotype of drug resistance through genotype, and the gene mutation of katG and embB shows significant regional differences. By now, there is no report on the mutation rate or mutation spectrum of those two genes in mycobacterium tuberculosis, whether katG315 and embB306 can be used as the marker to screen and test INH and EMB resistance of mycobacterium tuberculosis needs further exploration. Section 2 and Section 3 in this study used sequencing method to analyze the polymorphism of katG in 97 strains and embB in 101 strains of local patients by different compound drugs, and set a base to form a rapid molecular biological method to test INH resistance or EMB resistance in Chongqing. The main results and conclusions are as follows:
1. The general DR-TB rate and MDR-TB rate is 27.6% (301/1089) and 7.3% (79/1089); the DR-TB rate and MDR-TB rate for new case is 22.7% and 4.1%; and the DR-TB rate and MDR-TB rate for re-treatment is 56.2% and 26.5%. In general, Chongqing’s DR-TB level is in the middle level compared to the domestic or foreign surveillance results.
2. The resistance rates for SM, INH, RFP and EMB are 16.3%, 14.0%, 10.7% and 4.7% respectively. In the recent three years, RFP resistance, EMB resistance and multi-drug resistance are constantly rising.
3. Multi-drug resistance cases show no obvious gender of age difference, but they are closely related to chemotherapy history and living conditions (rural environment, annual income lower than average level etc.)
4. The distribution of (M)DR-TB cases indicated that epidemic spreading of (M)DR-TB might exist within a certain scope to some extent in some area of Chongqing, so it is necessary to reinforce the surveillance of drug resistance, especially at the molecular level, in order to diagnose the expansion of mycobacterium tuberculosis at an early stage, which is also important to control the epidemic situation of (M)DR-TB.
5. katG315 mutation spectra from INH resistant strains in Chongqing can be divided into three types: S315T, S315N and S315, with the general mutation 75.5% (37/49), including 81.1% (30/37) S315 mutation. katG315 mutation was not detected in INH sensitive strains.
6. Compared to the traditional drug sensitivity test, , the method by using katG315 as the INH-resistant marker showed a high sensitivity 75.5%, specificity 100% and accuracy 87.6% (85/97). And according to other indicators, such method showed a fair clinic application value.
7. katG315 mutation in MDR-TB strains was significantly higher than that in INH-resistant strains, and related to drug resistance quantity, so it is suitable to be used as the molecular marker for MDR-TB test.
8. The analysis of katG mutation spectrum indicated that katG315 mutation is the major molecular mechanism to generate the local INH resistance. No katG315 mutation was detected in 24.5% INH resistant strains, indicating that there were some other mechanisms in the local area to generate INH resistance. The influence of mutation other rare point positions on the generating process of INH resistance needs further study.
9. embB306 mutation rate in EMB-resistant strains (66.7%) was significantly higher than that in EMB-sensitive strains (60.0%). Compared to the traditional drug sensitivity test, the method by using embB306 as the EMB-resistant marker showed a high sensitivity 66.7%, specificity 90% and accuracy 78.2%, indicating that the rapid method by using embB306 mutation to test EMB resistant strains is applicable to the clinic.
10. embB306 mutation rate in EMB-resistant MDR strains (84.0%) was significantly higher than that in non-MDR strains (60.0%), and ascending with the growth of drug resistance quantity, indicating that embB306 is more suitable for testing EMB-resistant MDR strains as a marker.
11. embB mutation spectrum is in broad distribution. In the present study, embB306 mutation covered 66.7% EMB-resistant strains, indicating that embB306 mutation is the major molecular mechanism to generate EMB resistance in Chongqing, and that other molecular mechanisms are probably related to a number of rare mutations and the common results of all those rare mutations.
In conclusion, the present study outlined the baseline information and the major epidemic characteristics of (M)DR-TB in Chongqing, and identified that katG315 and embB306 are the major molecular mechanisms for INH resistance and EMB resistance respectively, so the method by using INH or EMB as the marker for rapid test of drug resistance shows a fair clinic application value. Besides, the results of this study also provides reference for prevention and control of TB, and (M)DR-TB in Chongqing
流行病学调查显示:通常经济和卫生、医疗条件等较差的地区,耐药结核病疫情尤为严重,同时结核病疫情和耐药结核病的流行病学特征存在明显的地区差异。重庆地处西南,农村人口多,经济不够发达,近10年尚无大样本量的耐(多)药结核病相关流行病学研究调查报道,因此了解本市耐(多)药结核病的相关基线资料和流行病学特征对于促进耐(多)药结核病的控制有重要意义。本研究第一部分,即是对在2003年~2006年在重庆市法定结核病防治机构(结核病防治所和胸科医院)连续收集的痰培养阳性的1089例结核病病例的耐药情况和流行病学特征进行分析。
异烟肼(Isoniazide,INH)和乙胺丁醇(ethambutol,EMB)是WHO推荐使用的一线抗结核组合药物之一。近年WHO/IUATLD在全球的结核病耐药监测结果显示:全球INH平均耐药率为5.6%,大多数国家和地区INH耐药率呈现逐年上升趋势,且在四种一线抗结核药物(INH,RFP,SM和EMB)中,INH耐药率在各国和地区均排列第一或第二位,我国INH耐药率为17.6%,耐药水平较高。全球平均EMB耐药率为0.8%(0~24.8),尽管总体耐药水平较低,但呈逐年快速上升趋势,我国EMB耐药率(1.5%)显著高于全球平均EMB耐药水平。INH和EMB耐药率的高企和升高,将明显影响WHO推荐的以此为主要组合药物方案治疗结核病的疗效。从降低耐药结核病病人死亡、减少传染源、缩短传染期的角度来看,早期诊断、早期选择敏感药物治疗耐药结核病病例是预防和控制耐(多)药结核病和减少卫生资源浪费的重要措施之一。但目前以培养为基础的药敏检测方法需要较长的时间(1~3月)才能得到结果,难以实现早期诊断和及时指导临床用药的目的。随着分子生物学理论和技术的发展,结核分枝杆菌INH耐药和EMB耐药的分子机制得到一定程度的阐明,目前研究已经证实结核分枝杆菌内编码活化INH所必需的过氧化氢酶-过氧化物的katG基因(尤其katG315)的变异是INH耐药性产生的最主要分子机制,但katG315在不同地区的INH耐药结核分枝杆菌中的变异率存在明显差异,从26%至95%不等。结核分枝杆菌中编码阿拉伯糖基转移酶的embB基因突变(尤其306位密码子)是引起结核分枝杆菌乙胺丁醇耐药的最主要原因, embB306突变覆盖约50%~70%的EMB耐药菌株,是目前与EMB耐药最相关的分子生物学标记物。部分地区已将katG315和embB306突变作为耐药分子标记物,采用PCR-FRLP和PCR-SSCP等方法进行临床INH和EMB耐药菌株的检测,实现了INH和EMB耐药病例的早期诊断和及时指导临床治疗,具有较高的特异性和敏感性,研究证明katG315、embB306分别在INH、EMB耐药结核杆菌中突变率较高的地区,这些快速、价廉的分子生物学方法在临床上应用是可行的。由于分子生物学检测方法是通过基因型来推测细菌耐药的表型,且katG基因和embB基因变异具有明显的地域分布特点,重庆地区尚无这两个基因在结核分枝杆菌中的突变谱、突变率的研究报道,katG315和embB306是否是本地区INH耐药、EMB耐药结核分枝杆菌的主要分子机制?是否可分别用于筛选或检测INH耐药、EMB耐药结核病的分子标记物?有待研究阐明。本研究第二部分和第三部分采用测序方法分别对重庆不同耐药组合的97株结核分枝杆菌中的katG基因和101株结核分枝杆菌中的embB基因的多态性及它们与耐药相关性进行了分析,将有助于阐明以上问题。主要结果和结论如下:
一、第一部分重庆市2003 ~2006年结核病耐药情况的流行病学调查
1.重庆市结核病总耐药率和耐多药率分别是27.6%(301/1089)和7.3%(79/1089);其中初治耐药率和耐多药率分别是22.7%、4.1%,复治耐药率和耐多药率分别是56.2%、26.5%。整体耐药水平与国内外监测结果比较,处于中等水平。
2. SM、INH、RFP、EMB耐药率分别是16.3%、14.0%、10.7%和4.7%;近3年RFP、EMB耐药率和耐多药率呈逐年上升趋势。
3.耐(多)药病例分布无明显性别和年龄特征,但与用药史、经济条件差(居住乡村、可支配年收入低于平均水平)存在较强联系。提示耐(多)药结核病防治应重点加强直接面视下督导短程化疗( Directly Observed Treatment Short course, DOTS)方案的实施和经济条件较差的结核病病例的规律全程治疗。
4.耐药病例的分布特征提示:重庆地区可能存在一定范围、一定程度的耐药结核分枝杆菌的传播,应加强结核病的耐药监测尤其分子水平的监测,有利于早期发现和预防耐药结核分枝杆菌大规模的扩散,对于控制耐(多)药结核病疫情有重要意义。
二、第二部分重庆市97株结核分枝杆菌的katG315突变特征及其与异烟肼耐药相关性的研究
1.重庆地区INH耐药结核分枝杆菌中katG315突变谱包括S315T、S315N和S315三种类型,总突变率为75.5%(37/49),其中81.1%(30/37)为S315T突变型,INH敏感菌株中未见katG315突变。katG315突变是本地区结核分枝杆菌INH耐药的主要分子机制。
2.以katG315突变做为诊断INH耐药菌株的标记物,与传统药敏试验比较,灵敏度为75.5%,特异度为100%,准确度为87.6%(85/97),其他各项评价指标均提示:在本地区,该指标用于INH耐药菌株的快速诊断具有较好的的临床应用价值。
3. katG315在高度耐药(1ug/ml)和耐多药菌株中的突变率分布分别显著高于低度耐药(0.2 ug/ml)和单耐INH菌株,且与耐药数量有关,一定程度上表明katG315突变与耐药程度有关。
4. katG突变率分析显示:katG315变异是本地区INH耐药产生的主要分子机制,24.5%的INH耐药株未见katG315变异,表明在本地区还存在其他INH耐药的分子机制,对于本地区结核病、耐药结核病的防治有一定参考价值。
三、第三部分重庆101株结核分枝杆菌的embB306突变特征及其与乙胺丁醇耐药相关性的研究
1. embB306在EMB耐药菌株中突变率有明显地域差异,重庆地区EMB耐药菌株中embB306突变率66.7%,34/51显著高于EMB敏感菌株的突变率(6.0%,3/50)(P〈0.01),与传统药敏实验比较,embB306突变作为EMB耐药标记物检测EMB耐药的灵敏度为66.7%(34/51),特异度为90%(45/50),准确度为78.2%(79/101)。提示在没有更好标记物情况下,embB306突变应用于本地区的EMB耐药菌株的检测有一定临床意义。
2. embB306在EMB耐药MDR菌株中突变率为84.0%(21/25)显著高于非MDR菌株中的突变率(50.0%,13/26),且突变率随耐药数量增加而增加,提示embB306突变与耐药程度有关。
3. embB突变谱较广泛,embB306突变覆盖66.7%(34/51)的EMB耐药菌株,提示embB306突变是本地区EMB耐药产生的主要分子机制,其他分子机制可能与大量稀少突变及其联合作用有关。
总之,通过本研究获得了重庆结核病耐药基线资料和耐药结核病的主要流行病学特征;同时明确了KatG315和embB306突变分别是本地区结核分枝杆菌INH、EMB耐药的主要分子机制,它们作为INH、EMB耐药快速检测的分子标记物具有一定临床应用价值。该研究结果对于本地区结核病、耐药结核病的防治有一定参考价值。
The incidence and infection of drug resistance tuberculosis (DR-TB), especially for the multi-drug resistance tuberculosis (MDR-TB) is one of the major cause to revive the epidemic of tuberculosis. WHO and IUATLD launched a global program for surveillance of drug resistance in 1994 to identify global DR-TB distribution, and conducted a resistance investigation on the first line drugs, including streptomycin(SM), isoniazid(INH) rifampicin (RFP) and ethambutol(EMB), among114 countries and area in the world from 1994 to 2003 to disclose the growing tendency of MDR-TB in developing countries. China is on the list of“Countries and Districts need more attention”proposed by WHO due to the severe situation of drug resistance. MDR-TB problem in China is also a“hot topic”.
The main task for TB control at present is to prevent and control MDT-TB, for which, the baseline information and epidemic characteristics of DT-TB shall be collected for reference to make preventive or administrative policies. However, both DR-TB information and epidemic characteristics show regional differences. Located in southwest, Chongqing is confronted with the pressure of large rural population and relatively underdeveloped economy. In the last decade, there is no local report on (M)DR-TB based on large sample size. In a word, the baseline information and epidemic characteristics of local (M)DR-TB is critical to DR-TB control. Section 1 in the present study disclosed smear positive samples sequentially collected by authorized local TB prevention organization (Tuberculosis Prevention and Control Institute, chest hospital etc.), total 1089 cases, and the analysis of drug resistant information and epidemic characteristics thereof.
INH and EMB are the first line TB resistance drugs recommended by WHO and one of the indispensable compound drugs for TB treatment. According to the global surveillance report on drug resistance tuberculosis by WHO, the resistance rate of INH is rising yearly around the world. Of all the four TB drugs (INH, RFP, SM and EMB), the resistance rate of INH is the highest or the second highest, 5.6% on average. China’s INH resistance rate is 17.6%, rather a high level. Generally speaking, the global EMB resistance rate is low, only 0.8% (0~24.8) on average, but rising rapidly every year. China’s EMB resistance rate (1.5%) is higher than the global average value.
To reduce death rate of DR-TB patients, infection sources and infection period, diagnosis and selection of sensitive drugs at the early stage is the most important method to help TB patients. However, the present drug sensitivity testing method based on culture is too time-consuming (1-3months) to be used in clinic timely. The developing molecular biological theories and techniques shed some light on the molecular mechanism of INH resistance and EMB resistance of mycobacterium tuberculosis. Up to now, researchers have proved that the mutation katG genes (especially katG315), an indispensible catalase- peroxide to INH activation by internal-coding of mycobacterium tuberculosis, is the major cause for INH resistance. Also the mutation rates of katG315 in INH-resistant mycobacterium tuberculosis shows regional differences (26%~95%). The mutation of embB (especially the 306th codon), the gene that is responsible for coding arabinose glycosyltransferase is the major cause to lead EMB resistance. embB 306 mutation was detected on 50%~70% EMB-resistant stains, so it is regarded as the molecular biological marker closely related to EMB resistance. katG315 mutation and embB306 mutation are used as the clinic testing methods for INH and EMB resistance respectively in some regions, by which the diagnosis and therapy of INF or EMB resistance are realized as well as showing high sensitivity and specificity. So it is safe to declare the feasibility of applying those rapid and economical molecular biological methods to clinic.
Molecular biology is to estimate the phenotype of drug resistance through genotype, and the gene mutation of katG and embB shows significant regional differences. By now, there is no report on the mutation rate or mutation spectrum of those two genes in mycobacterium tuberculosis, whether katG315 and embB306 can be used as the marker to screen and test INH and EMB resistance of mycobacterium tuberculosis needs further exploration. Section 2 and Section 3 in this study used sequencing method to analyze the polymorphism of katG in 97 strains and embB in 101 strains of local patients by different compound drugs, and set a base to form a rapid molecular biological method to test INH resistance or EMB resistance in Chongqing. The main results and conclusions are as follows:
1. The general DR-TB rate and MDR-TB rate is 27.6% (301/1089) and 7.3% (79/1089); the DR-TB rate and MDR-TB rate for new case is 22.7% and 4.1%; and the DR-TB rate and MDR-TB rate for re-treatment is 56.2% and 26.5%. In general, Chongqing’s DR-TB level is in the middle level compared to the domestic or foreign surveillance results.
2. The resistance rates for SM, INH, RFP and EMB are 16.3%, 14.0%, 10.7% and 4.7% respectively. In the recent three years, RFP resistance, EMB resistance and multi-drug resistance are constantly rising.
3. Multi-drug resistance cases show no obvious gender of age difference, but they are closely related to chemotherapy history and living conditions (rural environment, annual income lower than average level etc.)
4. The distribution of (M)DR-TB cases indicated that epidemic spreading of (M)DR-TB might exist within a certain scope to some extent in some area of Chongqing, so it is necessary to reinforce the surveillance of drug resistance, especially at the molecular level, in order to diagnose the expansion of mycobacterium tuberculosis at an early stage, which is also important to control the epidemic situation of (M)DR-TB.
5. katG315 mutation spectra from INH resistant strains in Chongqing can be divided into three types: S315T, S315N and S315, with the general mutation 75.5% (37/49), including 81.1% (30/37) S315 mutation. katG315 mutation was not detected in INH sensitive strains.
6. Compared to the traditional drug sensitivity test, , the method by using katG315 as the INH-resistant marker showed a high sensitivity 75.5%, specificity 100% and accuracy 87.6% (85/97). And according to other indicators, such method showed a fair clinic application value.
7. katG315 mutation in MDR-TB strains was significantly higher than that in INH-resistant strains, and related to drug resistance quantity, so it is suitable to be used as the molecular marker for MDR-TB test.
8. The analysis of katG mutation spectrum indicated that katG315 mutation is the major molecular mechanism to generate the local INH resistance. No katG315 mutation was detected in 24.5% INH resistant strains, indicating that there were some other mechanisms in the local area to generate INH resistance. The influence of mutation other rare point positions on the generating process of INH resistance needs further study.
9. embB306 mutation rate in EMB-resistant strains (66.7%) was significantly higher than that in EMB-sensitive strains (60.0%). Compared to the traditional drug sensitivity test, the method by using embB306 as the EMB-resistant marker showed a high sensitivity 66.7%, specificity 90% and accuracy 78.2%, indicating that the rapid method by using embB306 mutation to test EMB resistant strains is applicable to the clinic.
10. embB306 mutation rate in EMB-resistant MDR strains (84.0%) was significantly higher than that in non-MDR strains (60.0%), and ascending with the growth of drug resistance quantity, indicating that embB306 is more suitable for testing EMB-resistant MDR strains as a marker.
11. embB mutation spectrum is in broad distribution. In the present study, embB306 mutation covered 66.7% EMB-resistant strains, indicating that embB306 mutation is the major molecular mechanism to generate EMB resistance in Chongqing, and that other molecular mechanisms are probably related to a number of rare mutations and the common results of all those rare mutations.
In conclusion, the present study outlined the baseline information and the major epidemic characteristics of (M)DR-TB in Chongqing, and identified that katG315 and embB306 are the major molecular mechanisms for INH resistance and EMB resistance respectively, so the method by using INH or EMB as the marker for rapid test of drug resistance shows a fair clinic application value. Besides, the results of this study also provides reference for prevention and control of TB, and (M)DR-TB in Chongqing
引文
1. WHO. The world health report 2004: changing history. Geneva:World Health Organization, 2004.
2. Turrubiarte-Guillén N, Reyes-Morales H, Fernández-Cantón S, etal.Mortality due to selected causes of infectious and chronic non-transmissible diseases, from 1991 to 2004. Rev Med Inst Mex Seguro Soc. 2006;44( 1): 111-119.
3. Lopez AD, Mathers CD.Measuring the global burden of disease and epidemiological transitions: 2002-2030.Ann Trop Med Parasitol. 2006;100(5-6):481-99.
4. Farchi S,Mantovani J, Borgia P,et al.Tuberculosis incidence, hospitalisation prevalence and mortality in Lazio, Italy, 1997-2003. Int J Tuberc Lung Dis. 2008 ,12(2):193-8.
5. WHO.WHOreport on the tuberculosis epidemic, 1995. Stop TB at the source . Geneva: WHO,1995. Report No WHO/TB/95.183.
6. Frieden TR, Munsiff SS. The DOTS strategy for controlling the global tuberculosis epidemic. Clin Chest Med 2005; 26: 197–205.
7. WHO.The stop TB strategy, Building on and enhancing DOTS tomeet the TB-related millennium development goals. Geneva:WHO, 2006. Report No WHO/HTM/STB/ 2006.37.
8. WHO.Global tuberculosis control, surveillance, planning, financing .Geneva: WHO, 2007. Report No WHO/HTM/TB/2007.376.
9. Matteo Z, Mehran SH, Abigail W .et al.Global Incidence of Multidrug-Resistant Tuberculosis[J] The Journal of Infectious Diseases 2006; 194:479–85
10. Cardoso EM. Multiple drug resistance: a threat for tuberculosis control[J] .Rev Panam Salud Publica, 2004 ,16(1):68-73.
11. Erik C. B?ttger and Burkhard Springer. Tuberculosis: drug resistance, fitness, and strategies for global control. Eur J Pediatr.2008,167:141–148
12. Ellen M Zager and Ruth McNerney. Multidrug-resistant tuberculosis BMC Infectious Diseases 2008, 8:10
13. Kochi A, Vareldzis B, Styblo K. Multidrug resistant tuberculosis and its control. Res Microbiol 1993; 144: 104-110.
14. Bl?ndal, K., Barriers to reaching the targets for tuberculosis control: multidrug-resistant tuberculosis. Bull World Health Organ, 2007. 85(5): 387-90.
15. Catherine Kyobutungi, Abdhalah Kasiira Ziraba, Alex Ezeh,et al.The burden of disease profile of residents of Nairobi's slums: Results from a Demographic Surveillance System.Population Health Metrics 2008, 6:1
16. Coimbra CE Jr and Basta PC.The burden of tuberculosis in indigenous peoples in Amazonia, Brazil.Trans R Soc Trop Med Hyg. 2007 ;101(7):635-6.
17. Dye C, Scheele S, Dolin P, et al. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. JAMA 1999; 282: 677–86.
18. world Health Organization,International Union Against Tuberculosis and Lung Disease .Anti—tuberculosis drug resistance in the world :The WHO/IUATLD global project on anti—tuberculosis drug resistance surveillance. Geneva: WHO/IUATLD ,1997,1~120.
19. world Health Organization,International Union Against Tuberculosis and Lung Disease. Anti—tuberculosis drug resistance in the world :The WHO/IUATLD global project on anti—tuberculosis drug resistance surveillance. Report NO.2.Prevalence and Trends. Geneva: WHO/IUATLD ,2000,1~107
20. World Health Organisation: Anti-tuberculosis drug resistance in the world: Report Number 3. The WHO/IUALTD global project on anti-tuberculosis drug resistance surveillance. In: WHO/CDS/TB/2004.343. Geneva: WHO; 2004. (http://www.who. int/tb/publications/who_htm_tb_2004_343/en/index.html
21. World Health Organization. Anti-tuberculosis drug resistance in the world. Fourth global report. Geneva, Switzerland: World Health Organization; 2008. http://www. who.int/tb/publications/2008/drs_report4_26feb08.pdf.
22.刘宇红,姜广路,赵立平等.第四次全国结核病流行病学抽样调查—结核分枝杆菌耐药性分析与评价[J].中华结核和呼吸杂志2002 ,25 (4):224~227
23. world Health Organization Anti-tuberculosis drug resistance in the world report no3.WHO/HTM/TB/2004.343.http://www.who.int/tb/publications/who_htm_tb_2004_343/en/index.html
24. Graham S. Timmins and Vojo Deretic. Mechanisms of action of isoniazid. Molecular Microbiology (2006) 62(5), 1220–1227
25. Ng, VH, Cox, JS, Sousa, AO, et al. Role of katG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Mol Microbiol .2004;52: 1291–1302.
26. Argyrou, A., Vetting, M.W, Aladegbami, B.er al. Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. Nat Struct Mol Biol , 2006; 13:408–413.
27. Lancaster, J.R., Jr, and Gaston, B. NO and nitrosothiols:spatial confinement and free diffusion. Am J Physiol Lung Cell Mol Physiol.2004; 287: L465–L466.
28. Guo H, Seet Q, Denkin S,et al. Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA. J Med Microbiol. 2006 Nov;55(11):1527-31.
29. Caroline Lavender,Maria Globan,2Aina Sievers,et al.Molecular Characterization of Isoniazid-Resistant Mycobacterium tuberculosis Isolates Collected in Australia. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 2005, 49(10): 4068–4074.
30. Maxim V. Afanas’ev1, Larisa N. Ikryannikova, Elena N. Il’ina1, et al.Molecular characteristics of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis isolates from the Russian Federation. Journal of Antimicrobial Chemotherapy .2007,59:1057–1064
31. Saeed ZAKER BOSTANABAD, Leonid P. TITOV,et al.katG mutations in isoniazid-resistant strains of Mycobacterium tuberculosis isolates from Belarusian patients. Tüberküloz ve Toraks Dergisi 2007; 55(3): 231-237
32. Mokrousov I, Narvskaya O, Otten T,et al.High prevalence of katG Ser315Thr substitution among isoniazid-resistant Mycobacterium tuberculosis clinical isolates from northwestern Russia, 1996 to 2001.Antimicrob Agents Chemother. 2002 May;46(5):1417-24.
33. Maxine Caws, Dau Quang Tho, Phan Minh Duy,et al.PCR-Restriction Fragment Length Polymorphism for Rapid, Low-Cost Identification of Isoniazid-Resistant Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY, June 2007, 45(6):1789–1793.
34. Min Zhang,1Jun Yue, Yan-ping Yang,et al.Detection of Mutations Associated withIsoniazid Resistance in Mycobacterium tuberculosis Isolates from China .JOURNAL OF CLINICAL MICROBIOLOGY, Nov. 2005,43(11): 5477–5482
35. Raphael C. Y. Chan, Mamie Hui, Edward W. C.et al.Genetic and phenotypic characterization of drug-resistant Mycobacterium tuberculosis isolates in Hong Kong. Journal of Antimicrobial Chemotherapy. 2007,59, 866–873
36. Lenti A, Philipp WJ, Sreevatsan S, et al. The emb operon,a gene cluster of Mycobacteriumtuberculosis involved in resistance to ethambutol. Nature Medicine, 1997, 3(5):567-570.
37. Sreevatsan S,Stockbauer KE, Xi P,et al. Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob. Agents Chemother., 1997,41(8):1677-1681
38. Ramaswamys S, Amin Aq Goksel S, et al. Molecular genetic analysis of nucleotide polymorphisms associated with ethambutol resistance in human isolates of Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2000, 44(2):326-336
39. Hazbon MH, Bobadilla del Valle M, Guerrero MI, et al. Role of embB codon 306 mutations inMycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than etnambutol resistance. Antimicrob Agents Chemothe.r, 2005,49(9):3794-3802
40. Belanger AE, Besra GS, Ford ME, et al. The embAB genes of Mycobacterium avium encode an arabinosyl transferase involed in cell wall arabinan biosynthesis that is the target for the antimycobacterial ethambutol. Proc Natl Acad Sci USA, 1996, 93(21):11919-11924.
41. Mikusova K, Slayden RA , Besra GS , et al1Biogenesis of the mycobacterial cell wall and the site of action of ethambutol1 Antimicrob Agents Chemother ,1995 ,39 :2484~2489
42. Deng, L., Mikusova, K., Robuck, K.G., Scherman, M., Brennan,P.J., and McNeil, M.R. (1995). Recognition of multiple effectsof ethambutol on metabolism of mycobacterial cell envelope .Antimicrob. Agents Chemother. 39, 694–701.
43. Claudia Plinke, Sabine Ru¨sch-Gerdes, and Stefan Niemann. Significance of Mutations in embB Codon 306 for Prediction of Ethambutol Resistance in ClinicalMycobacterium tuberculosis Isolates.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2006, p. 1900–1902
44. Xin Shen, Guo-miao Shen, Jie Wu,et al.Association between embB Codon 306 Mutations and Drug Resistance in Mycobacterium tuberculosis. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007,51(7):. 2618–2620
45. WU Xueqiong, LIANG Jianqin, ZHANG Junxian,et al.Detection and evalua tion of the mutations of embB gene in ethambutol susceptible and resistant M ycobacterium tubercu losisisola tes from China.ChineseMedical Journal 2005; 118 (20) : 1739~1741
46. S. Ahmad, A. A. Jaber, E. Mokaddas.Frequency of embB codon 306 mutations in ethambutol-susceptible and -resistant clinical Mycobacterium tuberculosis isolates in Kuwait.Tuberculosis .2007, 87, 123–129.
47. Tatjana Tracevska , Inta Jansone , Anda Nodieva.ET AL.Characterisation of rpsL, rrs and embB mutations associated with streptomycin and ethambutol resistance in Mycobacterium tuberculosis.Research in Microbiology . 2004 ,155 :830–834
48.中国防痨协会.结核病诊断细菌学检验规程[J].中国防痨杂志,1996,18(1):28
49. World Health Organization (WHO). Guidelines for surveillance of drug resistance in tuberculosis. WHO/CDS/TB/2003.320.Geneva:WHO, 2003.
50.严碧涯主编.结核病学.北京出版社. 2003.第1版
51. World Health Organization.Global tuberculosis control - surveillance, planning, financing. WHO Report 2008. WHO/HTM/TB/2008.393. (http://www.who.int/tb/ publications/global_report/2008/en/index.html)
52.杜长梅,王国斌,徐吉英等.河南省第二轮结核病耐药监测及耐药趋势研究[J].中国防痨杂志2006 ,28(2):95~100
53.王民,张福生,端木宏谨.山东省耐药结核病流行状况研究[J].中华结核和呼吸杂志1999年12月第22卷第12期728~730.
54.李群,王晓萌,何海波等.WHO浙江省结核病耐药监测研究报告[J].中华结核和呼吸杂志. 2002,23(12)718~721.
55.钟球,钱明,李建伟等.广东省WHO结核病耐药监测研究[J].中国防痨杂志,2001年,23 (1):5~8.
56.李国明、吴兴荣、张缇等.湖北省结核分枝杆菌耐药性监测研究. [J].中华结核和呼吸杂志.2002 ,25(12):723~727.
57. Cheong SV, Lao U L .Epidemiological survey on the trend of drug resistance of Mycobacterium tuberculosis complex in Macao during 2001 to 2005. Zhonghua Jie He He Hu Xi Za Zhi. 2007;30(6):411-4.
58. Aung WW, Ti T, Than KK, et al.Study of drug resistant cases among new pulmonary tuberculosis patients attending a tuberculosis center, Yangon, Myanmar. Southeast Asian J Trop Med Public Health. 2007 ;38(1):104-10.
59. Javaid A, Hasan R, Zafar A,et al.Prevalence of primary multidrug resistance to anti-tuberculosis drugs in Pakistan. Int J Tuberc Lung Dis. 2008 Mar;12(3):326-31.
60. M. R. Joseph, C. T. Shoby, G. R. Amma,et al. Surveillance of anti-tuberculosis drug resistance in Ernakulam District, Kerala State, South India . NT J TUBERC LUNG DIS.2007. 11(4):443–449
61.胡代玉,汪涛,刘晓云等.重庆市涂阳肺结核病人直接面视下服药的实施现状与影响因素分析.中国卫生资源.2006;9(5):219~221.
62. Eliana DMA,Carlos ML,Carolina B et al. Anti-Tuberculosis Drug Resistance in Strains of Mycobacterium tuberculosis Isolated from Patients in a Tertiary Hospital in Bahia[J]. The Brazilian Journal of Infectious Diseases .2007;11(3):331-338
63. Albuquerque M.F., Leitao C.C., Campelo A.R, et al. Prognostic factors for pulmonary tuberculosis outcome in Recife,Pernambuco, Brazil. Rev Panam Salud Publica.2001;9(6):368-74.
64. Shi R, Itagaki N, Sugawara I.Overview of anti-tuberculosis (TB) drugs and their resistance mechanisms.Mini Rev Med Chem. 2007 ;7(11):1177-85.
65. Bai GH, Park YK, Choi YW.et al.Trend of anti-tuberculosis drug resistance in Korea, 1994-2004.Int J Tuberc Lung Dis. 2007 May;11(5):571-6
66.刘伟,司书毅,肖春玲.新型抗结核药物的研究进展.[J].国外医药抗生素分册.2006年,27(2):91~95
67. A. Alberte-Casti?eiras , M. F. Brezmes-Valdivieso , A.Campos-Bueno , et al .Drug-resistant tuberculosis in Castilla-León, Spain, 1996–2000.INT J TUBERC LUNG DIS 10(5):554–558
68. T. Ti, T. Lwin, T. T. Mar,et al.National anti-tuberculosis drug resistance survey,2002,in Myanmar. INT J TUBERC LUNG DIS 10(10):1111–1116.
69. Choi JC, Lim SY, Suh GY,et al.Drug Resistance Rates of Mycobacterium tuberculosis at a Private Referral Center in Korea .J Korean Med Sci. 2007; 22: 677-81
70. Davies J,Davis D D. Misreading of ribonucleic acid code words induced by aminoglycoside antibiotics. The effect of drug concentration[J].J Bio1 Chem, 1968, 243:3312
71. Tuberculosis Research Committee.Drug-resistant Mycobacterium tuberculosis in Japan: a nationwide survey, 2002. Int J Tuberc Lung Dis. 2007 ;11(10):1129-35.
72. Ernesto Montoro, Dihadenys Lemus, Miguel Echemend?′a,et al.Drug-resistant tuberculosis in Cuba. Results of the three global projects. Tuberculosis .2006, 86, 319–323
73. Khalequ Z, Zeaur R, Mohammad Y, et al.,Drug resistance of Mycobacterium tuberculosis in selected urban and rural areas in Bangladesh. Scandinavian Journal of Infectious Diseases, 2005; 37: 21~26
74. Migliori GB, Centis R, Fattorini L, et al. Monitoring the quality of laboratories and the prevalence of resistance to antituberculosis drugs: Italy, 1998–2000.Eur Respir J 2003;21:129–34
75. Girardi E, Antonucci G, Tronci M, et al. Drug resistance patterns among tuberculosis patients in Rome, 1990–1992. Scand J Infect Dis. 1996;28:487–91.
76. Helbling P, Altpeter E, Raeber P-A, et al. Surveillance of antituberculosis drug resistance in Switzerland 1995–1997: the central link. Eur Respir J.2000;16:200–2.
77. Djuretic T, Herbert J, Drobniewski F, et al. Antibiotic resistant tuberculosis in the United Kindom: 1993–1999. Thorax 2002;57:477–82
78. Zwolska Z, Augustynowicz-Kopec E, Klatt M. Primary and acquired drug resistance in Polish tuberculosis patients: results of a study of the national drug resistance surveillance programme. Int J Tuberc Lung Dis 2000;4:832–8.
79. Ruddy M, Balabanova Y, Graham C, et al. Rates of drug resistance and risk factor analysis in civilian and prison patients with tuberculosis in Samara Region, Russia. Thorax 2005;60:130–5.
80. Schaberg T, Glober G, Reichert B, et al. Drug-resistant pulmonary tuberculosis inBerlin, Germany, 1987–1993. Eur Respir J 1995;8:1067
81. Crudu V, Arnadottir Th, Laticevschi D. Resistance to anti-tuberculosis drugs and practices in drug susceptibility testing in Moldova, 1995–1999.Int J Tuberc Lung Dis .2003;7:336–42.
82. A Faustini, A J Hall, C A Perucci.Risk factors for multidrug resistant tuberculosis in Europe: a systematic review. Thorax 2006;61:158–163.
83. D. Falzon, A. Infuso,F. A?t-Belghiti.In the European Union, TB patients from former Soviet countries have a high risk of multidrug resistance. INT J TUBERC LUNG DIS .2006;10(9):954–958
84. C. M. Clark, J. Li, C. R. Driver, S. S. Munsiff.Risk factors for drug-resistant tuberculosis among non-US-born persons in New York City. INT J TUBERC LUNG DIS 2005;9(9):964–969
85. Migliori GB, Fattorini L, Vaccarino P, et al. Prevalence of resistance to antituberculosis drugs: results of the 1998/99 national survey in Italy. Int J TubercLung Dis .2002;6:32–8.
86. Kanavaki S , Mantadakis E , Nikolaou S.et al. Antimicrobial resistance of Mycobacterium tuberculosis isolates from children in Greece, 1994-2004. Int J Tuberc Lung Dis. 2007;11(4):424-8.
87. Khalilzadeh S, Boloorsaz MR.Primary and acquired drug resistance in childhood tuberculosis.East Mediterr Health J. 2006 Nov;12(6):909-14
88. De Souza MB, Antunes CM, Garcia GF.Multidrug-resistant Mycobacterium tuberculosis at a referral center for infectious diseases in the state of Minas Gerais, Brazil: sensitivity profile and related risk factors.J Bras Pneumol. 2006 ;32(5):430-7.
89.梅建,薛桢,沈鑫等.原发性耐药是耐药结核病产生的重要原因[J].中华结核和呼吸杂志,2006:29(2):75~79
90. Diz S, López-Vélez R, Moreno A, et al.Epidemiology and clinical features of tuberculosis in immigrants at an infectious diseases department in Madrid. Int J Tuberc Lung Dis. 2007 ;11(7):769-74.
91. Valérie Schwoebel, Bénédicte Decludt, Anne-Claire de Benoist,et al.Multidrug resistant tuberculosis in France 1992-4:two case-control studies. BMJ. 1998 Sep 5;317(7159):630-1.
92. Escalante, P, S. Ramaswamy, H. Sanabria, H, et al. Genotypic characterization of drug-resistant Mycobacterium tuberculosis isolates.from Peru. Tuberc. Lung Dis. 1998;79:111–118.
93. Jun-ichiro Sekiguchi, Tohru Miyoshi-Akiyama, Ewa Augustynowicz-Kopec ,et al. Detection of Multidrug Resistance in Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY, Jan. 2007, 179–192
94. M. Caws, Phan Minh Duy,et al.Dau Quang Tho,et al.Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam. JOURNAL OF CLINICAL MICROBIOLOGY. 2007, 179–192
95. Igor Mokrousov, Olga Narvskaya, Tatiana Otten, et al.High Prevalence of katG Ser315Thr Substitution among Isoniazid Resistant Mycobacterium tuberculosis Clinical Isolates from Northwestern Russia, 1996 to 2001. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2002, 1417–1424
96. Rosilene Fressatti Cardoso, Marco Antonio Cardoso, Clarice Queico Fujimura Leite,et al. Characterization of ndh gene of isoniazid resistant and susceptible Mycobacterium tuberculosis isolates from Brazil. Mem Inst Oswaldo Cruz, Rio de Janeiro, 2007Vol. 102(1): 59-61
97. Saeed Zakerbostanabad , Leonid Petrovich Titov , Ahmad R. Bahrmand,et al.Frequency and molecular characterization of isoniazid resistance in katG region of MDR isolates from tuberculosis patients in southern endemic border of Iran. Infection, Genetics and Evolution .2008; 8: 15–19.
98. Shu-Lin Zhang , Hua Qi , Dun-Lian Qiu , et al.Genotypic Analysis of Multidrug-Resistant Mycobacterium tuberculosis Isolates Recovered From Central China. Biochemical Genetics,2007;45(3):312~319
99.程晓东,文彬,苏明权,等多重聚合酶链反应检测结核菌耐异烟肼相关基因.第四军医大学学报.2003 ;24 (9):849~851
100. Zhang Y, Heym B, Allen B, Young D et a1.The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature. 1992 , 358(6387): 591-593
101. Vilchèze C, Jacobs WR Jr.The mechanism of isoniazid killing: clarity through the scope of genetics.Annu Rev Microbiol. 2007;61:35-50.
102. He X, Alian A, Ortiz de Montellano PR.Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.Bioorg Med Chem. 2007 Nov 1;15(21):6649-58.
103. Kruh NA, Rawat R, Ruzsicska BP, Tonge PJ.Probing mechanisms of resistance to the tuberculosis drug isoniazid: Conformational changes caused by inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis.Protein Sci. 2007 ,16(8):1617-27
104. Tonge PJ, Kisker C, Slayden RA.Development of modern InhA inhibitors to combat drug resistant strains of Mycobacterium tuberculosis.Curr Top Med Chem. 2007;7(5):489-98.
105. Chen X, Ma Y, Jin Q,et al.Characterization of the katG, inhA, ahpC, kasA, and oxyR gene mutations in isoniazid-resistant and susceptible strain of Mycobacterium tuberculosis by automated DNA sequencing.Zhonghua Jie He He Hu Xi Za Zhi. 2005 Apr;28(4):250-3.
106. Barry CE , Slayden RA , Mdluli K.Mechanisms of isoniazid resistance in Mycobacterium tuberculosis.Drug Resist Updat. 1998;1(2):128-34.
107. Scarpellini P, Carrera P, Cichero P,et al.Detection of resistance to isoniazid by denaturing gradient-gel electrophoresis DNA sequencing in Mycobacterium tuberculosis clinical isolates.New Microbiol. 2003 Oct;26(4):345-51.
108. Kremer L, Dover LG, Morbidoni HR, et al.Inhibition of InhA activity, but not KasA activity, induces formation of a KasA-containing complex in mycobacteria.J Biol Chem. 2003;278(23):20547-54.
109. Mdluli K, Slayden RA, Zhu Y,et al.Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid.Science. 1998;280(5369):1607-11.
110. Kremer L, Dover LG, Morbidoni HR,et al.Inhibition of InhA activity, but not KasA activity, induces formation of a KasA-containing complex in mycobacteria.J Biol Chem. 2003;278(23):20547-54.
111. Abal AT, Ahmad S, Mokaddas E. Variations in the occurrence of the S315T mutation within the katG gene in isoniazid-resistant clinical Mycobacterium tuberculosis isolates from Kuwait. Microb Drug Resist 2002,8(2): 99-105.
112. Marttila HJ, Soini H, Eerola E et al. A Ser315Thr substitution in katG ispredominant in genetically heterogeneous multidrug-resistant Mycobacterium tuberculosis isolates originating from the St. Petersburg area in Russia. Antimicrob Agents Chemother. 1998, 42(9):2443-2445.
113. Van Soolingen D, De Haas PE, Van Doorn HR, et al. Mutations at amino acid position 3 l5 of the katG gene are associated with high-level resistance to isoniazid, other drug resistance , and successful transmission of Mycobacterium tuberculosis in the Netherlands. J Infect Dis 2000,182(6):1788一1790.
114. Sajduda A, Brzostek A, Poplawska M,et al. Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Poland. J Clin Microbiol. 2004, 42(6):2425-2431.
115. Silva M SN, Senna S G Ribeiro M O, et al. Mutations in katG, inhA, and ahpC Genes of Brazilian Isoniazid-Resistant Isolates of Mycobacterium tuberculosis. J Clin Microbiol, 2003, 41(9): 4471一4474.
116. Wojtyczka RD, Dworniczak S, Pacha J,et al.PCR-RFLP analysis of a point mutation in codons 315 and 463 of the katG gene of Mycobacterium tuberculosis isolated from patients in Silesia, Poland.Pol J Microbiol. 2004;53(2):89-93.
117. Wengenack NL, Lane BD, Hill PJ,et al.Purification and characterization of Mycobacterium tuberculosis katG, katG(S315T), and Mycobacterium bovis katG(R463L).Protein Expr Purif. 2004 Aug;36(2):232-43
118.张宗德,贾红艳,古淑香等.结核分枝杆菌kat G基因第463位密码子突变与异烟肼耐药的研究。中华结核和呼吸杂志1999 ;22(3):35~38
119. Soo-Young Kim, Yeon-Joon Park, Won-Il Kim,et al.Molecular analysis of isoniazid resistance in Mycobacterium tuberculosis isolates recovered from South Korea.Diagnostic Microbiology and Infectious Disease. 2003, 47: 497–502.
120. Florence Brossier, Nicolas Veziris, Chantal Truffot-Pernot,et al. Performance of the Genotype MTBDR Line Probe Assay for Detection of Resistance to Rifampin and Isoniazid in Strains of Mycobacterium tuberculosis with Low- and High-Level Resistance. JOURNAL OF CLINICAL MICROBIOLOGY , 2006 , 44(10): 3659–3664
121. Wilson K.Preparation of genomic DNA from bacteria.Curr Protoc Mol Biol. 2001 Nov;Chapter 2:Unit 2.4.
122. Oliveira CG, Martinez RA, Gaiotto FA.DNA extraction from bristles and quills of Chaetomys subspinosus (Rodentia: Erethizontidae) using a novel protocol.Genet Mol Res. 2007 Sep 30;6(3):657-66.
123. Wendy Somerville, Louise Thibert, Kevin Schwartzman,et al.Extraction of Mycobacterium tuberculosis DNA: a Question of Containment. JOURNAL OF CLINICAL MICROBIOLOGY, 2005, 2996–2997
124. WU Xue-qiong,LU Yang, ZHANG Jun-xian,et al.Detection of the mutations in katG315 and inhA-15 of Mycobacterium tuberculosis strains isolated from Chinese patients. Chin Med J 2006; 119 (3):230 :230-233
125. Manzour Hernando Hazbo′n, Michael Brimacombe, Miriam Bobadilla del Valle,et al.Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 2006, 50(8):2640–2649
126.金嘉琳、张文宏、翁心华等.华东地区耐药结核分枝杆菌katG基因的变异.中华传染病学杂志.2006.24(5)301~306.
127. M. Caws, Phan Minh Duy, Dau Quang Tho ,et al.Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam. JOURNAL OF CLINICAL MICROBIOLOGY, 2006, 44(7): 2333–2337 .
128. A. Nusrath Unissa, N. Selvakumar, Sujatha Narayanan, P.R,et al. Molecular analysis of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from India.. International Journal of Antimicrobial Agents . 2008, 71–75
129. H?fling CC, Pavan EM, Giampaglia CM,et al. Prevalence of katG Ser315 substitution and rpoB mutations in isoniazid-resistant Mycobacterium tuberculosis isolates from Brazil.Int J Tuberc Lung Dis. 2005;9(1):87-93
130. H?fling CC, Pavan EM, Giampaglia CM,et al. Prevalence of katG Ser315 substitution and rpoB mutations in isoniazid-resistant Mycobacterium tuberculosis isolates from Brazil.Int J Tuberc Lung Dis. 2005 Jan;9(1):87-93
131. Soo-Young Kim, Yeon-Joon Park, Won-Il Kim,et al.Molecular analysis of isoniazid resistance in Mycobacterium tuberculosis isolates recovered from South Korea.Diagnostic Microbiology and Infectious Disease. 2003, 47: 497–502.
132. Liselotte Aristimu?o , Raimond Arm , Alberto Cebollada , et al.Molecular characterisation of Mycobacterium tuberculosis isolates in the First National Survey of Anti-tuberculosis Drug Resistance from Venezuela. BMC Microbiology 2006, 6:90~112.
133. Z. FANG,C. DOIG,A. RAYNER,et al.Molecular Evidence for Heterogeneity of the Multiple-Drug-Resistant Mycobacterium tuberculosis Population in Scotland (1990 to 1997). OURNAL OF CLINICAL MICROBIOLOGY.1999, 37(4):998–1003
134. HARRI J. MARTTILA, HANNA SOINI, PENTTI HUOVINEN, AND MATTI K. VILJANEN.katG Mutations in Isoniazid-Resistant Mycobacterium tuberculosis Isolates Recovered from Finnish Patients. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1996, 2187–2189.
135. G. Tudó, J. González, R. Obama,et al.Study of resistance to anti-tuberculosis drugs in five districts of Equatorial Guinea: rates, risk factors, genotyping of gene mutations and molecular epidemiology. INT J TUBERC LUNG DIS 2004 ,8(1):15–22
136. Telenti A, Honore N, Bernasconi C,et al. Genotypic assessment of isoniazid and rifampin resistance in Mycobacterium tuberculosis: a blind study at reference laboratory level. J Clin Microbiol.1997, 35, 719–723
137. Piatek, AS, Telenti, A, Murray, MR, et al.. Genotypic analysis of Mycobacterium tuberculosis in two distinct populations using molecular beacons: implications for rapid susceptibility testing. Antimicrob Agents.Chemother .2000;44, 103–110.
138. Abate, Hoffner, S E, Thomsen, V O,et al. Characterization of isoniazid-resistant strains of Mycobacterium tuberculosis on the basis of phenotypic properties and mutations in katG. Eur J Clin Microbiol Infect Dis .2001;20:329–333.
139. Kiepiela, P, Bishop, K. S, Smith, A. N,et al.Genomic mutations in the katG, inhA and ahpC genes are useful for the prediction of isoniazid resistance in Mycobacterium tuberculosis isolates from Kwazulu Natal, South Africa. Tuber Lung Dis .2000;80:47–56.
140. Marttila HJ, Soini HE , Vyshnevskaya E, et al. A Ser315Thr substitution in katG is predominant in genetically heterogeneous multidrug-resistant Mycobacteriumtuberculosis isolates originating from the St. Petersburg area in Russia. Antimicrob Agents Chemoter. 1998, 42,2443–2445.
141. Lonnroth, K, L. M. Thuong, K. Lambregts, et al. Private tuberculosis care provision associated with poor treatment outcome: comparative study of a semi-private lung clinic and the NTP in two urban districts in Ho Chi Minh City, Vietnam. National Tuberculosis Programme.Int. J. Tuberc. Lung Dis. 2003 ,7:165–171
142. ELIF AKTAS,RIZA DURMAZ,DONG YANG,et al.Molecular Characterization of Isoniazid and Rifampin Resistance of Mycobacterium tuberculosis Clinical Isolatesfrom Malatya, Turkey. MICROBIAL DRUG RESISTANCE Volume 11, Number 2, 2005,94~99
143. Lee A. S., S. N. Othman, Y. M. Ho, and S. Y. Wong. Novel mutations within the embB gene in ethambutol-susceptible clinical isolates of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2004;48:4447–4449
144. Mokrousov, I, T. Otten, B. Vyshnevskiy, and O. Narvskaya. Detection of embB306 mutations in ethambutol-susceptible clinical isolates of Mycobacterium tuberculosis from Northwestern Russia: implications for genotypic resistance testing. J. Clin. Microbiol. 2002;40:3810–3813.
145. Beggs WH , Andrews FA.Nonspecific inhibition of ethambutol binding by Mycobacterium smegmatis1Antimicrob Agents Chemother ,1973;4 : 1152~1191
146. Deng L,Miknsova K, Robuck KG, et al.Recognition of multiple effects of ethambutol on metabolism of mycobacterial cell envelope. Antimicrob Agents Chemother .1995;39 :6942~7011
147. Kilburn JQ ,Takayama K,Armstrong EL ,et al1Effects of ethambutol on phospholipid metabolism in Mycobacterium smegmatis1Antimicrob AgentsChemother. 1981;19 :346~348
148. Silve G,Guillen PV ,Quemard A ,et al 1Ethambutol inhibition of glucose metabolism in mycobacteria : a possible target of the drug1 Antimicrob Agents Chemother .1993 ,37 :1536~1538.
149. Takayama K, Kilburn JO. Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis. Antimicrob Agents Chemother .1989 ,33 :1493~1499
150. Wolucka BA , Mcneil MR , deHoffmann E , et al1Recognition of the lipidintermediate for arabinan arabinogalactan biosynthesis and its relation to the mode of action of ethambutol on mycobacteria1. J Biol Chem.1994 ;269 :23328~23335.
151. Mikusova K, Slayden RA , Besra GS , et al1Biogenesis of the mycobacterial cell wall and the site of action of ethambutol Antimicrob. Agents Chemother.1995;39 :2484~2489.
152. Jagannath, C, V. M. Reddy, and P. R. Gangadharam. 1995. Enhancement of drug susceptibility of multi-drug resistant strains of Mycobacterium tuberculosis by ethambutol and dimethyl sulphoxide. J. Antimicrob. Chemother. 1995;35:381–390.
153. Sharma K, Gupta M, Pathak M,et al.Transcriptional control of the mycobacterial embCAB operon by PknH through a regulatory protein, EmbR, in vivo. J Bacteriol. 2006;188(8):2936-44.
154. Molle V, Reynolds RC, Alderwick LJ,et al.EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR. Biochem J. 2008;410(2):309-17.
155. Zheng X, Papavinasasundaram KG, Av-Gay Y,et al.Novel substrates of Mycobacterium tuberculosis PknH Ser/Thr kinase. Biochem Biophys Res Commun. 2007 ; 355(1):162-8.
156. H. Rinder, K. T. Mieskes, E. Tortoli.et al. Detection of embB codon 306 mutations in ethambutol resistant Mycobacterium tuberculosis directly from sputum samples: a low-cost, rapid approach. Molecular and Cellular Probes.2001,15,37–42
157. Igor Mokrousov, Tatiana Otten, Boris Vyshnevskiy,et al.Detection of embB306 Mutations in Ethambutol-Susceptible Clinical Isolates of Mycobacterium tuberculosis from Northwestern Russia: Implications for Genotypic Resistance Testing. JOURNAL OF CLINICAL MICROBIOLOGY. 2002,40(10):3810~3813.
158. Manzour Hernando Hazbon,1Miriam Bobadilla del Valle, Marta In?′rida Guerrero,et al.Role of embB Codon 306 Mutations in Mycobacterium tuberculosis Revisited: a Novel Association with Broad Drug Resistance and IS6110 Clustering Rather than Ethambutol Resistance .Antimicrobial gents and chemotherapy.2005;49(9): 3794–3802.
159. Jun-ichiro Sekiguchi, Tohru Miyoshi-Akiyama, Ewa Augustynowicz-Kopec,et al.Detection of Multidrug Resistance in Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY.2007;45(1):179–192 .
160. Ahmad S,Mokaddas E, Jaber AA, et al. Rapid detection of ethambutol-resistant Mycobacterium tuberculosis strains by PCR-RFLP targeting embB codons 306 and 497 and iniA codon 501 mutations. Mol. Cell. Probes. 2004. 18,299–306.
161. Laszlo A, Rahman M, Raviglione M, et al. Quality assurance programme for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Laboratory Network: first round of proficiency testing. Int J Tuberc Lung Dis 1997; 1: 231–238.
162. R. Johnson, A. M. Jordaan, L. Pretorius,E,et al.Ethambutol resistance testing by mutation detection. INT J TUBERC LUNG DIS. 2006,10(1):68–73.
163. Laszlo A, Rahman M, Raviglione M, et al. Quality assurance programme for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Laboratory Network: first round of proficiency testing. Int J Tuberc Lung Dis 1997; 1: 231–238.
164. S. Srivastava, A. Garg,1A. Ayyagari, et al.Nucleotide Polymorphism Associated with Ethambutol Resistance in Clinical Isolates of Mycobacterium tuberculosis.CURRENT MICROBIOLOGY . 2006,53:401–405
165. Daniela Isola, Manuela Pardinib, Francis Varaine,et al.A Pyrosequencing assay for rapid recognition of SNPs in Mycobacterium tuberculosis embB306 region.Journal of Microbiological Methods .2005,62: 113– 120
166. Sugawara I, Otomo K, Yamada H,et al.The molecular epidemiology of ethambutol-resistant Mycobacterium tuberculosis in Henan Province. Jpn J Infect Dis. 2005 ,58(6):393~395
167. J-R. Zhao, Y-J. Bai, Y. Wang, et al.Development of a pyrosequencing approach for rapid screening of rifampin, isoniazid and ethambutol-resistant Mycobacterium tuberculosis. Int J tuberclung dis.2006:328–332
168. Linda M. Parsons,Max Salfinger, Anne Clobridge,et al.Phenotypic and Molecular Characterization of Mycobacterium tuberculosis Isolates Resistant to both Isoniazid and Ethambutol. Antimicrobial gents and chemotherapy. 2005;49(6): 2218~2225
169. Srinivas V. Ramaswamy , Shu-Jun Dou , et al.Genotypic analysis of multidrug-resistant Mycobacterium tuberculosis isolates from Monterrey , Mexico.Journal of Medical Microbiology.2004;53:107~113
170. Mukaigawa J, Endoh M, Yanagawa Y,et al. Anti-drug pattern of drug-resistant Mycobacterium tuberculosis and analysis of mutation in drug-target genes.Kansenshogaku Zasshi. 2005;79(6):388~96
171. Igor Mokrousov, N. Vijaya Bhanu, Philip N. Suffys.et al.Multicenter evaluation of reverse line blot assay for detection of drug resistance in Mycobacterium tuberculosis clinical isolates.Journal of Microbiological Methods. 2004;57:323~ 335
172. Ann S. G. Lee, Siti Noor Khadijah Othman, Yu Min Ho,et al.Novel Mutations within the embB Gene in Ethambutol-Susceptible Clinical Isolates of Mycobacterium tuberculosis. Antimicrobial gents and chemotherapy. 2004;48(11):4447~4449 .
1. WHO. The world health report 2004: changing history. Geneva:World Health Organization, 2004.
2. Turrubiarte-Guillén N, Reyes-Morales H, Fernández-Cantón S, etal.Mortality due to selected causes of infectious and chronic non-transmissible diseases, from 1991 to 2004. Rev Med Inst Mex Seguro Soc. 2006;44( 1): 111-119.
3. Lopez AD, Mathers CD.Measuring the global burden of disease and epidemiological transitions: 2002-2030.Ann Trop Med Parasitol. 2006;100(5-6):481-99.
4. Farchi S, Mantovani J, Borgia P,et al.Tuberculosis incidence, hospitalisation prevalence and mortality in Lazio, Italy, 1997-2003. Int J Tuberc Lung Dis. 2008 ,12(2):193-8.
5. Cardoso EM. Multiple drug resistance: a threat for tuberculosis control[J] .Rev Panam Salud Publica, 2004 ,16(1):68-73.
6. Erik C. B?ttger and Burkhard Springer. Tuberculosis: drug resistance, fitness, and strategies for global control. Eur J Pediatr.2008,167:141–148
7. Ellen M Zager and Ruth McNerney. Multidrug-resistant tuberculosis .BMC Infectious Diseases. 2008, 8:10.
8. world Health Organization,International Union Against Tuberculosis and Lung Disease .Anti—tuberculosis drug resistance in the world :The WHO/IUATLD global project on anti—tuberculosis drug resistance surveillance. Geneva: WHO/IUATLD ,1997,1~120.
9. World Health Organization (WHO). Guidelines for surveillance of drug resistance in tuberculosis. WHO/CDS/TB/2003.320.Geneva:WHO, 2003.
10. world Health Organization,International Union Against Tuberculosis and Lung Disease. Anti—tuberculosis drug resistance in the world :The WHO/IUATLD global project on anti—tuberculosis drug resistance surveillance. Report NO.2.Prevalence and Trends. Geneva: WHO/IUATLD ,2000,1~107
11. Catherine Kyobutungi, Abdhalah Kasiira Ziraba, Alex Ezeh,et al.The burden of disease profile of residents of Nairobi's slums: Results from a Demographic Surveillance System.Population Health Metrics 2008, 6:1
12. Coimbra CE Jr and Basta PC.The burden of tuberculosis in indigenous peoples in Amazonia, Brazil.Trans R Soc Trop Med Hyg. 2007 ;101(7):635-6.
13. Dye C, Scheele S, Dolin P, et al. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. JAMA 1999; 282: 677–86.
14. Zhang Y, Heym B, Allen B, Young D et a1.The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature. 1992 ,358(6387):591-593
15. Graham S. Timmins and Vojo Deretic. Mechanisms of action of isoniazid. Molecular Microbiology .2006; 62(5): 1220–1227
16. Ng, V.H, Cox, J.S., Sousa, A.O, et al. Role of katG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Mol Microbiol .2004;52: 1291–1302.
17. Argyrou, A., Vetting, M.W, Aladegbami, B.er al. Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. Nat Struct Mol Biol , 2006; 13:408–413.
18. Lancaster, J.R., Jr, and Gaston, B. NO and nitrosothiols:spatial confinement and free diffusion. Am J Physiol Lung Cell Mol Physiol.2004; 287: 465–466
19. Vilchèze C, Jacobs WR Jr.The mechanism of isoniazid killing: clarity through the scope of genetics.Annu Rev Microbiol. 2007;61:35-50.
20. He X, Alian A, Ortiz de Montellano PR.Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.Bioorg MedChem. 2007 Nov 1;15(21):6649-58.
21. Kruh NA, Rawat R, Ruzsicska BP, Tonge PJ.Probing mechanisms of resistance to the tuberculosis drug isoniazid: Conformational changes caused by inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis.Protein Sci. 2007 ,16(8):1617-27
22. Tonge PJ, Kisker C, Slayden RA.Development of modern InhA inhibitors to combat drug resistant strains of Mycobacterium tuberculosis.Curr Top Med Chem. 2007;7(5):489-98.
23. Chen X, Ma Y, Jin Q,et al.Characterization of the katG, inhA, ahpC, kasA, and oxyR gene mutations in isoniazid-resistant and susceptible strain of Mycobacterium tuberculosis by automated DNA sequencing.Zhonghua Jie He He Hu Xi Za Zhi. 2005 Apr;28(4):250-3.
24. Barry CE , Slayden RA , Mdluli K.Mechanisms of isoniazid resistance in Mycobacterium tuberculosis.Drug Resist Updat. 1998;1(2):128-34.
25. Scarpellini P, Carrera P, Cichero P,et al.Detection of resistance to isoniazid by denaturing gradient-gel electrophoresis DNA sequencing in Mycobacterium tuberculosis clinical isolates.New Microbiol. 2003 Oct;26(4):345-51.
26. Kremer L, Dover LG, Morbidoni HR, et al.Inhibition of InhA activity, but not KasA activity, induces formation of a KasA-containing complex in mycobacteria.J Biol Chem. 2003;278(23):20547-54.
27. Mdluli K, Slayden RA, Zhu Y,et al.Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid.Science. 1998;280(5369):1607-11
28. Saeed Zakerbostanabad , Leonid Petrovich Titov , Ahmad R. Bahrmand,et al.Frequency and molecular characterization of isoniazid resistance in katG region of MDR isolates from tuberculosis patients in southern endemic border of Iran. Infection, Genetics and Evolution .2008; 8: 15–19.
29. Maxim V. Afanas’ev1, Larisa N. Ikryannikova, Elena N. Il’ina1, et al.Molecular characteristics of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis isolates from the Russian Federation. Journal of Antimicrobial Chemotherapy .2007,59:1057–1064
30. Saeed ZAKER BOSTANABAD, Leonid P. TITOV,et al.katG mutations inisoniazid-resistant strains of Mycobacterium tuberculosis isolates from Belarusian patients. Tüberküloz ve Toraks Dergisi 2007; 55(3): 231-237
31. Mokrousov I, Narvskaya O, Otten T,et al.High prevalence of katG Ser315Thr substitution among isoniazid-resistant Mycobacterium tuberculosis clinical isolates from northwestern Russia, 1996 to 2001.Antimicrob Agents Chemother. 2002 May;46(5):1417-24.
32. Maxine Caws, Dau Quang Tho, Phan Minh Duy,et al.PCR-Restriction Fragment Length Polymorphism for Rapid, Low-Cost Identification of Isoniazid-Resistant Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY, June 2007, 45(6):1789–1793.
33. Min Zhang,1Jun Yue, Yan-ping Yang,et al.Detection of Mutations Associated with Isoniazid Resistance in Mycobacterium tuberculosis Isolates from China .JOURNAL OF CLINICAL MICROBIOLOGY, Nov. 2005,43(11): 5477–5482
34. Raphael C. Y. Chan, Mamie Hui, Edward W. C.et al.Genetic and phenotypic characterization of drug-resistant Mycobacterium tuberculosis isolates in Hong Kong. Journal of Antimicrobial Chemotherapy. 2007,59, 866–873
35. Herrera L , Valverde A , Saiz P , et al. Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis clinical strains isolated in the Philippines[J]. Int J Antimicrob Agents. 2004 ,23(6):572-6.
36. Shu-Lin Zhang , Hua Qi , Dun-Lian Qiu , et al.Genotypic Analysis of Multidrug-Resistant Mycobacterium tuberculosis Isolates Recovered From Central China. Biochemical Genetics, 2007;45(3-4):281-90.
37. H?fling CC, Pavan EM, Giampaglia CM,et al. Prevalence of katG Ser315 substitution and rpoB mutations in isoniazid-resistant Mycobacterium tuberculosis isolates from Brazil.Int J Tuberc Lung Dis. 2005 Jan;9(1):87-93
38. Soo-Young Kim, Yeon-Joon Park, Won-Il Kim,et al.Molecular analysis of isoniazid resistance in Mycobacterium tuberculosis isolates recovered from South Korea.Diagnostic Microbiology and Infectious Disease. 2003, 47: 497–502.
39. Jun-ichiro Sekiguchi, Tohru Miyoshi-Akiyama, Ewa Augustynowicz-Kopec,et al. Detection of Multidrug Resistance in Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY, 2007, 45(1): 179–192
40. Liselotte Aristimu?o , Raimond Arm , Alberto Cebollada , et al.Molecular characterisation of Mycobacterium tuberculosis isolates in the First National Survey of Anti-tuberculosis Drug Resistance from Venezuela. BMC Microbiology 2006, 6:90~112.
41. Zhang Y, GarbeuT , Young D1 Transformation with katGrestores isoniazid - sensitivity in Mycobacterium tuberculosis isolates resistant to arange of drug concentrations1 Mol Microbiol , 1994 , 8 : 521– 524.
42. Abal AT, Ahmad S, Mokaddas E. Variations in the occurrence of the S315T mutation within the katG gene in isoniazid-resistant clinical Mycobacterium tuberculosis isolates from Kuwait. Microb Drug Resist 2002,8(2): 99-105.
43. Marttila HJ, Soini H, Eerola E et al. A Ser315Thr substitution in katG is predominant in genetically heterogeneous multidrug-resistant Mycobacterium tuberculosis isolates originating from the St. Petersburg area in Russia. Antimicrob Agents Chemother. 1998, 42(9):2443-2445.
44. Van Soolingen D, De Haas PE, Van Doorn HR, et al. Mutations at amino acid position 3 l5 of the katG gene are associated with high-level resistance to isoniazid, other drug resistance , and successful transmission of Mycobacterium tuberculosis in the Netherlands. J Infect Dis 2000,182(6):1788一1790.
45. Sajduda A, Brzostek A, Poplawska M,et al. Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Poland. J Clin Microbiol. 2004, 42(6):2425-2431.
46. Silva M SN, Senna S G Ribeiro M O, et al. Mutations in katG, inhA, and ahpC Genes of Brazilian Isoniazid-Resistant Isolates of Mycobacterium tuberculosis. J Clin Microbiol, 2003, 41(9): 4471一4474.
47. Wojtyczka RD, Dworniczak S, Pacha J,et al.PCR-RFLP analysis of a point mutation in codons 315 and 463 of the katG gene of Mycobacterium tuberculosis isolated from patients in Silesia, Poland.Pol J Microbiol. 2004;53(2):89-93.
48. Wengenack NL, Lane BD, Hill PJ,et al.Purification and characterization of Mycobacterium tuberculosis katG , katG(S315T) , and Mycobacterium bovis katG(R463L).Protein Expr Purif. 2004 Aug;36(2):232-43
49.张宗德,贾红艳,古淑香等.结核分枝杆菌kat G基因第463位密码子突变与异烟肼耐药的研究。中华结核和呼吸杂志1999 ;22(3):35~38
50. Maxim V. Afanas’ev1, Larisa N. Ikryannikova, Elena N. Il’ina1, et al.Molecular characteristics of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis isolates from the Russian Federation. Journal of Antimicrobial Chemotherapy .2007,59:1057–1064.
51. Z. FANG,C. DOIG,.A. RAYNER,et al.Molecular Evidence for Heterogeneity of the Multiple-Drug-Resistant Mycobacterium tuberculosis Population in Scotland (1990 to 1997). OURNAL OF CLINICAL MICROBIOLOGY.1999, 37(4):998–1003
52. HARRI J. MARTTILA, HANNA SOINI, PENTTI HUOVINEN, AND MATTI K. VILJANEN.katG Mutations in Isoniazid-Resistant Mycobacterium tuberculosis Isolates Recovered from Finnish Patients. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1996, 2187–2189.
53.金嘉琳、张文宏、翁心华等.华东地区耐药结核分枝杆菌katG基因的变异.中华传染病学杂志.2006.24(5)301~306.
54. WU Xue-qiong,LU Yang, ZHANG Jun-xian,et al.Detection of the mutations in katG315 and inhA-15 of Mycobacterium tuberculosis strains isolated from Chinese patients. Chin Med J 2006; 119 (3):230 :230-233
55. JIAO Wei-wei, Mokrousov Igor, SUN Gui-zhi, et al.Molecular characteristics of rifampin and isoniazid resistant Mycobacterium tuberculosis strains from Beijing, China. Chin Med J 2007;120(814 9):814-819
56.王海英,刘志敏,郑建礼等.结核杆菌异烟肼表型耐药与katG基因突变相关性研究.齐鲁医学检验2005 ,16 (5 ):31~35
57. JIAO Wei-wei, Mokrousov Igor, SUN Gui-zhi, et al.Molecular characteristics of rifampin and isoniazid resistant Mycobacterium tuberculosis strains from Beijing, China. Chin Med J 2007;120(814 9):814-819.
58. Xin Ma, Haiying Wang, Yunfeng Deng,et al.rpoB Gene Mutations and Molecular Characterization of Rifampin-Resistant Mycobacterium tuberculosis Isolates from Shandong Province, China. JOURNAL OF CLINICAL MICROBIOLOGY, Sept. 2006, 44, 3409–3412
59. Saeed ZAKER BOSTANABAD , Ahmadreza BAHRMAND , Leonid Pet al.Identification of mutations in the rpoB encoding the RNA polymerase beta subunitin rifampicine-resistant Mycobacterium tuberculosis strains from Iran. Tüberküloz ve Toraks Dergisi 2007; 55(4): 370-377.
60. M. Caws, Phan M D,Dau Quang Tho,et al.Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam. JOURNAL OF CLINICAL MICROBIOLOGY.2006;44:2333–2337
61. Valim AR,Rossetti ML,Ribeiro MO,et al.Mutations in the rpoB gene of multidrug resisitant Mycobacterium tuberculosis isolates from Brazil[J].J Clin Microbiol. 2000,38:3119～3122.
62. Ahmad S, Mokaddas E,Farees E. Characterization of rpoB mutation in rifampin resisitant clinical Mycobacterium tuberculosis isolates from Kuwait and Dubai[J]. Diagn Microbiol Infect Dis, 2002,44(3):245~250
63. Ahmad S, Mokaddas E,Farees E. Characterization of rpoB mutation in rifampin resisitant clinical Mycobacterium tuberculosis isolates from Kuwait and Dubai[J]. Diagn Microbiol Infect Dis, 2002,44(3):245~250
64. Sajduda A, Brzostek A, Poplawska M, et al. Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Poland[J]. J Clin Microbiol. 2004 ,42(6):2425-31.
65. Tesic J, Lepsanovic Z, Mirovic V. Evaluation of usefulness of single-strand conformation polymorphism method for rapid detection of rifampicin-resistant Mycobacterium tuberculosis[J]. Vojnosanit Pregl. 2004 ,61(2):169-72.
66.葛超荣,林瑞炮,陈智等.结核分枝杆菌耐多药性与rpoB及katG基因关系的初步研究[J].中华结核和呼吸杂志.2003;26(4):245~249
67. Sajduda A, Brzostek A, Poplawska M, et al. Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Poland[J]. J Clin Microbiol. 2004;42(6):2425-31.
68. Ruiru Shi , Jianyuan Zhang , Chuanyou Li , et al.Detection of streptomycin resistance in Mycobacterium tuberculosis clinical isolates from China as determined by denaturing HPLC analysis and DNA sequencing. Microbes and Infection .2007;9:1538~1544.
69. T. Hosaka, J. Xu, K. Ochi, Increased expression of ribosome recycling factor is responsible for the enhanced protein synthesis during the late growth phase in anantibiotic-overproducing Streptomyces coelicolor ribosomal rpsL mutant, Mol. Microbiol. 2006;61: 883~897.
70. A. Brzostek, A. Sajduda, T. Sliwinski, et al.Molecular characterization of streptomycin-resistant Mycobacterium tuberculosis strains isolated in Poland,Int. J. Tuberc. Lung Dis. 8 (2004) 1032e1035.
71. Sharma D, Cukras AR, Rogers EJ, et al.Mutational analysis of S12 protein and implications for the accuracy of decoding by the ribosome.J Mol Biol. 2007;374(4):1065-76.
72. Tracevska T, Jansone I, Nodieva A et al.Characterisation of rpsL, rrs and embB mutations associated with streptomycin and ethambutol resistance in Mycobacterium tuberculosis[J]. Res Microbiol. 2004 ,55(10):830-834.
73. Springer B, Kidan YG, Prammanan T, et al. Mechanisms of streptomycin resistance: selection of mutations in the 16SrRNA gene conferring resistance[J]. Antimicrob Agents Chemother.2001,45(10):2877-2884.
74. Brzostek A, Sajduda A, Sliwinski T, et al. Molecular characterisation of streptomycin-resistant Mycobacterium tuberculosis strains isolated in Poland[J]. Int J Tuberc Lung Dis. 2004 ,8(8):1032-1035.
75. Lee AS, Tang LL, Lim IH, et al. Characterization of pyrazinamide and of loxacin resistance among drug resistanct Mycobacterium tuberculosis isolates from Singapore[J]. Int J infect Dis , 2002,6(1):48-51.
76. Miyagi C, Yamane N, Yogesh B, et al.Genetic and phenotypic characterization of pyrazinamide-resistant mycobacterium tuberculosis complex isolates in Japan[J]. Diagn Microbiol Infect Dis. 2004 ,48(2):111-6.
77. Endoh T, Yagihashi A, Uehara N, Kobayashi D, Pyrazinamide resistance associated with pncA gene mutation in Mycobacterium tuberculosis in Japan[J]. Epidemiol Infect. 2002 ,128(2):337-42.
78. Scorpio A, Lindholm LP, Heifetes L, et al.Characterization of pncA mutations in pyrazinamide resistant Mycobacterium tuberculosis[J]. Antimicrob Agenta Chemother, 1997,41(3):540-543.
79. Telenti A, Philipp WJ, Sreevatsan S, et al. The emb operon,a gene cluster of Mycobacteriumtuberculosis involved in resistance to ethambutol. Nature Medicine,1997, 3(5):567-570
80. Sreevatsan S, Stockbauer KE, Xi P, et al. Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob. Agents Chemother., 1997,41(8):1677-1681
81. Ramaswamys S, Amin Aq Goksel S, et al. Molecular genetic analysis of nucleotide polymorphisms associated with ethambutol resistance in human isolates of Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2000, 44(2):326-336
82. Hazbon MH, Bobadilla del Valle M, Guerrero MI, et al. Role of embB codon 306 mutations inMycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than etnambutol resistance. Antimicrob Agents Chemothe.r, 2005,49(9):3794-3802
83. Belanger AE, Besra GS, Ford ME, et al. The embAB genes of Mycobacterium avium encode an arabinosyl transferase involed in cell wall arabinan biosynthesis that is the target for the antimycobacterial ethambutol. Proc Natl Acad Sci USA, 1996, 93(21):11919-11924.
84. Mikusova K, Slayden RA , Besra GS , et al1Biogenesis of the mycobacterial cell wall and the site of action of ethambutol1 Antimicrob Agents Chemother ,1995 ,39 :2484~2489
85. Deng, L, Mikusova, K, Robuck, KG, et al. Recognition of multiple effectsof ethambutol on metabolism of mycobacterial cell envelope .Antimicrob. Agents Chemother. 1995: 39: 694–701.
86. Claudia Plinke, Sabine Ru¨sch-Gerdes, and Stefan Niemann. Significance of Mutations in embB Codon 306 for Prediction of Ethambutol Resistance in Clinical Mycobacterium tuberculosis Isolates. Antimicrobial gents and chemotherapy .2006; 37(2):1900–1902
87. Xin Shen, Guo-miao Shen, Jie Wu,et al.Association between embB Codon 306 Mutations and Drug Resistance in Mycobacterium tuberculosis. Antimicroboal Agnts and chemotherapy. 2007;51(7):. 2618–2620
88. Hazbon, M. H, M. Bobadilla del Valle, M. I. Guerrero, et al. Role of embB codon
306 mutations in Mycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than ethambutol resistance.AntimicrobAgents Chemother. 2005.49:3794–3802.
89. S. Ahmad, A. A. Jaber, E. Mokaddas.Frequency of embB codon 306 mutations in ethambutol-susceptible and -resistant clinical Mycobacterium tuberculosis isolates in Kuwait.Tuberculosis .2007; 87:123–129.
90. Escuyer, V. E, M. A. Lety, J. B. Torrelles, K. H,et al.The role of the embA and embB gene products in the biosynthesis of the terminal hexaarabinofuranosyl motif of Mycobacterium smegmatis arabinogalactan.J. Biol. Chem. 2001.276:48854–48862.
91. Jagannath, C, V. M. Reddy, and P. R. Gangadharam. 1995. Enhancement of drug susceptibility of multi-drug resistant strains of Mycobacterium tuberculosis by ethambutol and dimethyl sulphoxide. J. Antimicrob. Chemother. 1995.35:381–39
92.严碧涯主编结核病学北京出版社2003第1版
93. Rindi L, Lari N, Bonanni D,et al. Detection of Mycobacterium tuberculosis genotypic groups by a duplex real-time PCR targeting the katG and gyrA genes[J]. J Microbiol Methods. 2004 ,59(2):283-7
94. Post FA, Willcox PA, Mathema B,et al. Genetic polymorphism in Mycobacterium tuberculosis isolates from patients with chronic multidrug-resistant tuberculosis[J]. J Infect Dis. 2004 ,190(1):99-106
95. Ramaswamy SV, Dou SJ, Rendon A. Genotypic analysis of multidrug-resistant Mycobacterium tuberculosis isolates from Monterrey, Mexico[J]. J Med Microbiol. 2004 ,53(2):107-113
96.梁建琴.吴雪琼.曹立雪,等.应用膜反向斑点杂交技术快速检测结核分枝杆菌耐乙胺丁醇基因型的研究[J].微生物学报,2004,44(2):215～219
97. Yoshikawa Y, Ichihara T, Suzuki Y .Detection of drug-resistant Mycobacterium tuberculosis isolates using DNA microarray[J]. Rinsho Biseibutshu Jinsoku Shindan Kenkyukai Shi. 2003,14(1):45-50.
98. World Health Organisation: Anti-tuberculosis drug resistance in the world: Report Number 3. The WHO/IUALTD global project on anti-tuberculosis drug resistance surveillance. In: WHO/CDS/TB/2004.343. Geneva: WHO; 2004.(http://www.who.int/tb/publications/who_htm_tb_2004_343/en/index.html
99. World Health Organization. Anti-tuberculosis drug resistance in the world. Fourth global report. Geneva , Switzerland: World Health Organization; 2008.http://www.who.int/tb/publications/2008/drs_report4_26feb08.pdf
100.刘宇红,姜广路,赵立平等.第四次全国结核病流行病学抽样调查—结核分枝杆菌耐药性分析与评价[J].中华结核和呼吸杂志.2002;25 (4):224~227
101. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998; 393(6685):537-544.
102. Finken M, Kirschner只Meier A, et al. Molecular basis of streptomycin resistance in Mycobacterium tuberculosis: alterations of the ribosomal protein S12 gene and point mutations within a functional 16S ribosomal pseudolcnot. Mol Microbiol.1993;9(6):1239-1246.
103. Zhang Y. Telenti A. Genetics of drug resistance in Mycobacterium tuberculosis.Hatfull G. Jacobs W R, Molecular genetics of mycobacteria [M],Washington D. C:AMS Press. 2000:35
104. Ainsa J A, Martin C, Gicquel B, et al. Gomz一Lus. Characterization of the chromosomal aminoglycoside 2’-N-acetyltrans-ferase gene from Mycobacterium fortuitium[J].Antimicrob Agents Chemother. 1996;40:2350
105. Zhang Y.Mitchison D. The curious characteristics of pyrazinamide:a review [J].Int J Tuberc Lung Dis. 2003; 7:6
106. Zhang H, Deng JY, Bi LJ,et al.Characterization of Mycobacterium tuberculosis nicotinamidase/pyrazinamidase. FEBS J. 2008 ;275(4):753-62.
107. Chan RC, Hui M, Chan EW,et al.Genetic and phenotypic characterization of drug-resistant Mycobacterium tuberculosis isolates in Hong Kong. J Antimicrob Chemother. 2007 ;59(5):866-73.
108. Somoskovi A, Dormandy J, Parsons LM,et al.Sequencing of the pncA gene in members of the Mycobacterium tuberculosis complex has important diagnostic applications: Identification of a species-specific pncA mutation in "Mycobacterium canettii" and the reliable and rapid predictor of pyrazinamide resistance. J Clin Microbiol. 2007;45(2):595-9.
109. Barco P, Cardoso RF, Hirata RD,et al.pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis clinical isolates from the southeast region of Brazil. J Antimicrob Chemother. 2006;58(5):930-5.
110. Denkin S, Volokhov D, Chizhikov V,et al.Microarray-based pncA genotyping ofpyrazinamide-resistant strains of Mycobacterium tuberculosis. J Med Microbiol. 2005 ;54(12):1127-31
111. Morris S,Bai GH,Suffys P,et al. Moleculars mechanisms of multiple drug resistance in clinical isolates of Mycobacterium tuberculosis. J Infect Dis,1995;171:954一960.
112.庄玉辉.结核分枝杆菌耐药性分子机理研究若干进展.中华结核和呼吸杂志.1997;20(6):329一331.
113.胡忠义,靳安佳,景奉香,等.结核分枝杆菌耐多药的基因研究.中华检验医学杂志. 2001;24(20):73~75
114.吴雪琼,庄玉辉,张俊仙,等.耐多药结核病耐药分子机制的研究.中华结核和呼吸杂志.1997;20:332一335.
115. Jun-ichiro Sekiguchi, Tohru Miyoshi-Akiyama, Ewa Augustynowicz-Kopec,et al.Detection of Multidrug Resistance in Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY.. 2007;179–192.
116. Lipin MY, Stepanshina VN,Shemyakin IG, et al.Association of specific mutations in katG , rpoB , rpsL and rrs genes with spoligotypes of multidrug-resistant Mycobacterium tuberculosis isolates in Russia. Clin Microbiol Infect. 2007;13(6):620-626.
117. Davies J,Davis D D. Misreading of ribonucleic acid code words induced by aminoglycoside antibiotics. The effect of drug concentration[J].J Bio1 Chem, 1968, 243:3312
118. Garvin R T.Biswas U K , Gorini L.Che effects of streptomycin or dihydrostreptomycin binding to 16S rRNA or to 30S ribosomal subunits[J].Proc Nail Acad Sci USA,1974,71:3814
2. Turrubiarte-Guillén N, Reyes-Morales H, Fernández-Cantón S, etal.Mortality due to selected causes of infectious and chronic non-transmissible diseases, from 1991 to 2004. Rev Med Inst Mex Seguro Soc. 2006;44( 1): 111-119.
3. Lopez AD, Mathers CD.Measuring the global burden of disease and epidemiological transitions: 2002-2030.Ann Trop Med Parasitol. 2006;100(5-6):481-99.
4. Farchi S,Mantovani J, Borgia P,et al.Tuberculosis incidence, hospitalisation prevalence and mortality in Lazio, Italy, 1997-2003. Int J Tuberc Lung Dis. 2008 ,12(2):193-8.
5. WHO.WHOreport on the tuberculosis epidemic, 1995. Stop TB at the source . Geneva: WHO,1995. Report No WHO/TB/95.183.
6. Frieden TR, Munsiff SS. The DOTS strategy for controlling the global tuberculosis epidemic. Clin Chest Med 2005; 26: 197–205.
7. WHO.The stop TB strategy, Building on and enhancing DOTS tomeet the TB-related millennium development goals. Geneva:WHO, 2006. Report No WHO/HTM/STB/ 2006.37.
8. WHO.Global tuberculosis control, surveillance, planning, financing .Geneva: WHO, 2007. Report No WHO/HTM/TB/2007.376.
9. Matteo Z, Mehran SH, Abigail W .et al.Global Incidence of Multidrug-Resistant Tuberculosis[J] The Journal of Infectious Diseases 2006; 194:479–85
10. Cardoso EM. Multiple drug resistance: a threat for tuberculosis control[J] .Rev Panam Salud Publica, 2004 ,16(1):68-73.
11. Erik C. B?ttger and Burkhard Springer. Tuberculosis: drug resistance, fitness, and strategies for global control. Eur J Pediatr.2008,167:141–148
12. Ellen M Zager and Ruth McNerney. Multidrug-resistant tuberculosis BMC Infectious Diseases 2008, 8:10
13. Kochi A, Vareldzis B, Styblo K. Multidrug resistant tuberculosis and its control. Res Microbiol 1993; 144: 104-110.
14. Bl?ndal, K., Barriers to reaching the targets for tuberculosis control: multidrug-resistant tuberculosis. Bull World Health Organ, 2007. 85(5): 387-90.
15. Catherine Kyobutungi, Abdhalah Kasiira Ziraba, Alex Ezeh,et al.The burden of disease profile of residents of Nairobi's slums: Results from a Demographic Surveillance System.Population Health Metrics 2008, 6:1
16. Coimbra CE Jr and Basta PC.The burden of tuberculosis in indigenous peoples in Amazonia, Brazil.Trans R Soc Trop Med Hyg. 2007 ;101(7):635-6.
17. Dye C, Scheele S, Dolin P, et al. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. JAMA 1999; 282: 677–86.
18. world Health Organization,International Union Against Tuberculosis and Lung Disease .Anti—tuberculosis drug resistance in the world :The WHO/IUATLD global project on anti—tuberculosis drug resistance surveillance. Geneva: WHO/IUATLD ,1997,1~120.
19. world Health Organization,International Union Against Tuberculosis and Lung Disease. Anti—tuberculosis drug resistance in the world :The WHO/IUATLD global project on anti—tuberculosis drug resistance surveillance. Report NO.2.Prevalence and Trends. Geneva: WHO/IUATLD ,2000,1~107
20. World Health Organisation: Anti-tuberculosis drug resistance in the world: Report Number 3. The WHO/IUALTD global project on anti-tuberculosis drug resistance surveillance. In: WHO/CDS/TB/2004.343. Geneva: WHO; 2004. (http://www.who. int/tb/publications/who_htm_tb_2004_343/en/index.html
21. World Health Organization. Anti-tuberculosis drug resistance in the world. Fourth global report. Geneva, Switzerland: World Health Organization; 2008. http://www. who.int/tb/publications/2008/drs_report4_26feb08.pdf.
22.刘宇红,姜广路,赵立平等.第四次全国结核病流行病学抽样调查—结核分枝杆菌耐药性分析与评价[J].中华结核和呼吸杂志2002 ,25 (4):224~227
23. world Health Organization Anti-tuberculosis drug resistance in the world report no3.WHO/HTM/TB/2004.343.http://www.who.int/tb/publications/who_htm_tb_2004_343/en/index.html
24. Graham S. Timmins and Vojo Deretic. Mechanisms of action of isoniazid. Molecular Microbiology (2006) 62(5), 1220–1227
25. Ng, VH, Cox, JS, Sousa, AO, et al. Role of katG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Mol Microbiol .2004;52: 1291–1302.
26. Argyrou, A., Vetting, M.W, Aladegbami, B.er al. Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. Nat Struct Mol Biol , 2006; 13:408–413.
27. Lancaster, J.R., Jr, and Gaston, B. NO and nitrosothiols:spatial confinement and free diffusion. Am J Physiol Lung Cell Mol Physiol.2004; 287: L465–L466.
28. Guo H, Seet Q, Denkin S,et al. Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA. J Med Microbiol. 2006 Nov;55(11):1527-31.
29. Caroline Lavender,Maria Globan,2Aina Sievers,et al.Molecular Characterization of Isoniazid-Resistant Mycobacterium tuberculosis Isolates Collected in Australia. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 2005, 49(10): 4068–4074.
30. Maxim V. Afanas’ev1, Larisa N. Ikryannikova, Elena N. Il’ina1, et al.Molecular characteristics of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis isolates from the Russian Federation. Journal of Antimicrobial Chemotherapy .2007,59:1057–1064
31. Saeed ZAKER BOSTANABAD, Leonid P. TITOV,et al.katG mutations in isoniazid-resistant strains of Mycobacterium tuberculosis isolates from Belarusian patients. Tüberküloz ve Toraks Dergisi 2007; 55(3): 231-237
32. Mokrousov I, Narvskaya O, Otten T,et al.High prevalence of katG Ser315Thr substitution among isoniazid-resistant Mycobacterium tuberculosis clinical isolates from northwestern Russia, 1996 to 2001.Antimicrob Agents Chemother. 2002 May;46(5):1417-24.
33. Maxine Caws, Dau Quang Tho, Phan Minh Duy,et al.PCR-Restriction Fragment Length Polymorphism for Rapid, Low-Cost Identification of Isoniazid-Resistant Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY, June 2007, 45(6):1789–1793.
34. Min Zhang,1Jun Yue, Yan-ping Yang,et al.Detection of Mutations Associated withIsoniazid Resistance in Mycobacterium tuberculosis Isolates from China .JOURNAL OF CLINICAL MICROBIOLOGY, Nov. 2005,43(11): 5477–5482
35. Raphael C. Y. Chan, Mamie Hui, Edward W. C.et al.Genetic and phenotypic characterization of drug-resistant Mycobacterium tuberculosis isolates in Hong Kong. Journal of Antimicrobial Chemotherapy. 2007,59, 866–873
36. Lenti A, Philipp WJ, Sreevatsan S, et al. The emb operon,a gene cluster of Mycobacteriumtuberculosis involved in resistance to ethambutol. Nature Medicine, 1997, 3(5):567-570.
37. Sreevatsan S,Stockbauer KE, Xi P,et al. Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob. Agents Chemother., 1997,41(8):1677-1681
38. Ramaswamys S, Amin Aq Goksel S, et al. Molecular genetic analysis of nucleotide polymorphisms associated with ethambutol resistance in human isolates of Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2000, 44(2):326-336
39. Hazbon MH, Bobadilla del Valle M, Guerrero MI, et al. Role of embB codon 306 mutations inMycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than etnambutol resistance. Antimicrob Agents Chemothe.r, 2005,49(9):3794-3802
40. Belanger AE, Besra GS, Ford ME, et al. The embAB genes of Mycobacterium avium encode an arabinosyl transferase involed in cell wall arabinan biosynthesis that is the target for the antimycobacterial ethambutol. Proc Natl Acad Sci USA, 1996, 93(21):11919-11924.
41. Mikusova K, Slayden RA , Besra GS , et al1Biogenesis of the mycobacterial cell wall and the site of action of ethambutol1 Antimicrob Agents Chemother ,1995 ,39 :2484~2489
42. Deng, L., Mikusova, K., Robuck, K.G., Scherman, M., Brennan,P.J., and McNeil, M.R. (1995). Recognition of multiple effectsof ethambutol on metabolism of mycobacterial cell envelope .Antimicrob. Agents Chemother. 39, 694–701.
43. Claudia Plinke, Sabine Ru¨sch-Gerdes, and Stefan Niemann. Significance of Mutations in embB Codon 306 for Prediction of Ethambutol Resistance in ClinicalMycobacterium tuberculosis Isolates.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2006, p. 1900–1902
44. Xin Shen, Guo-miao Shen, Jie Wu,et al.Association between embB Codon 306 Mutations and Drug Resistance in Mycobacterium tuberculosis. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007,51(7):. 2618–2620
45. WU Xueqiong, LIANG Jianqin, ZHANG Junxian,et al.Detection and evalua tion of the mutations of embB gene in ethambutol susceptible and resistant M ycobacterium tubercu losisisola tes from China.ChineseMedical Journal 2005; 118 (20) : 1739~1741
46. S. Ahmad, A. A. Jaber, E. Mokaddas.Frequency of embB codon 306 mutations in ethambutol-susceptible and -resistant clinical Mycobacterium tuberculosis isolates in Kuwait.Tuberculosis .2007, 87, 123–129.
47. Tatjana Tracevska , Inta Jansone , Anda Nodieva.ET AL.Characterisation of rpsL, rrs and embB mutations associated with streptomycin and ethambutol resistance in Mycobacterium tuberculosis.Research in Microbiology . 2004 ,155 :830–834
48.中国防痨协会.结核病诊断细菌学检验规程[J].中国防痨杂志,1996,18(1):28
49. World Health Organization (WHO). Guidelines for surveillance of drug resistance in tuberculosis. WHO/CDS/TB/2003.320.Geneva:WHO, 2003.
50.严碧涯主编.结核病学.北京出版社. 2003.第1版
51. World Health Organization.Global tuberculosis control - surveillance, planning, financing. WHO Report 2008. WHO/HTM/TB/2008.393. (http://www.who.int/tb/ publications/global_report/2008/en/index.html)
52.杜长梅,王国斌,徐吉英等.河南省第二轮结核病耐药监测及耐药趋势研究[J].中国防痨杂志2006 ,28(2):95~100
53.王民,张福生,端木宏谨.山东省耐药结核病流行状况研究[J].中华结核和呼吸杂志1999年12月第22卷第12期728~730.
54.李群,王晓萌,何海波等.WHO浙江省结核病耐药监测研究报告[J].中华结核和呼吸杂志. 2002,23(12)718~721.
55.钟球,钱明,李建伟等.广东省WHO结核病耐药监测研究[J].中国防痨杂志,2001年,23 (1):5~8.
56.李国明、吴兴荣、张缇等.湖北省结核分枝杆菌耐药性监测研究. [J].中华结核和呼吸杂志.2002 ,25(12):723~727.
57. Cheong SV, Lao U L .Epidemiological survey on the trend of drug resistance of Mycobacterium tuberculosis complex in Macao during 2001 to 2005. Zhonghua Jie He He Hu Xi Za Zhi. 2007;30(6):411-4.
58. Aung WW, Ti T, Than KK, et al.Study of drug resistant cases among new pulmonary tuberculosis patients attending a tuberculosis center, Yangon, Myanmar. Southeast Asian J Trop Med Public Health. 2007 ;38(1):104-10.
59. Javaid A, Hasan R, Zafar A,et al.Prevalence of primary multidrug resistance to anti-tuberculosis drugs in Pakistan. Int J Tuberc Lung Dis. 2008 Mar;12(3):326-31.
60. M. R. Joseph, C. T. Shoby, G. R. Amma,et al. Surveillance of anti-tuberculosis drug resistance in Ernakulam District, Kerala State, South India . NT J TUBERC LUNG DIS.2007. 11(4):443–449
61.胡代玉,汪涛,刘晓云等.重庆市涂阳肺结核病人直接面视下服药的实施现状与影响因素分析.中国卫生资源.2006;9(5):219~221.
62. Eliana DMA,Carlos ML,Carolina B et al. Anti-Tuberculosis Drug Resistance in Strains of Mycobacterium tuberculosis Isolated from Patients in a Tertiary Hospital in Bahia[J]. The Brazilian Journal of Infectious Diseases .2007;11(3):331-338
63. Albuquerque M.F., Leitao C.C., Campelo A.R, et al. Prognostic factors for pulmonary tuberculosis outcome in Recife,Pernambuco, Brazil. Rev Panam Salud Publica.2001;9(6):368-74.
64. Shi R, Itagaki N, Sugawara I.Overview of anti-tuberculosis (TB) drugs and their resistance mechanisms.Mini Rev Med Chem. 2007 ;7(11):1177-85.
65. Bai GH, Park YK, Choi YW.et al.Trend of anti-tuberculosis drug resistance in Korea, 1994-2004.Int J Tuberc Lung Dis. 2007 May;11(5):571-6
66.刘伟,司书毅,肖春玲.新型抗结核药物的研究进展.[J].国外医药抗生素分册.2006年,27(2):91~95
67. A. Alberte-Casti?eiras , M. F. Brezmes-Valdivieso , A.Campos-Bueno , et al .Drug-resistant tuberculosis in Castilla-León, Spain, 1996–2000.INT J TUBERC LUNG DIS 10(5):554–558
68. T. Ti, T. Lwin, T. T. Mar,et al.National anti-tuberculosis drug resistance survey,2002,in Myanmar. INT J TUBERC LUNG DIS 10(10):1111–1116.
69. Choi JC, Lim SY, Suh GY,et al.Drug Resistance Rates of Mycobacterium tuberculosis at a Private Referral Center in Korea .J Korean Med Sci. 2007; 22: 677-81
70. Davies J,Davis D D. Misreading of ribonucleic acid code words induced by aminoglycoside antibiotics. The effect of drug concentration[J].J Bio1 Chem, 1968, 243:3312
71. Tuberculosis Research Committee.Drug-resistant Mycobacterium tuberculosis in Japan: a nationwide survey, 2002. Int J Tuberc Lung Dis. 2007 ;11(10):1129-35.
72. Ernesto Montoro, Dihadenys Lemus, Miguel Echemend?′a,et al.Drug-resistant tuberculosis in Cuba. Results of the three global projects. Tuberculosis .2006, 86, 319–323
73. Khalequ Z, Zeaur R, Mohammad Y, et al.,Drug resistance of Mycobacterium tuberculosis in selected urban and rural areas in Bangladesh. Scandinavian Journal of Infectious Diseases, 2005; 37: 21~26
74. Migliori GB, Centis R, Fattorini L, et al. Monitoring the quality of laboratories and the prevalence of resistance to antituberculosis drugs: Italy, 1998–2000.Eur Respir J 2003;21:129–34
75. Girardi E, Antonucci G, Tronci M, et al. Drug resistance patterns among tuberculosis patients in Rome, 1990–1992. Scand J Infect Dis. 1996;28:487–91.
76. Helbling P, Altpeter E, Raeber P-A, et al. Surveillance of antituberculosis drug resistance in Switzerland 1995–1997: the central link. Eur Respir J.2000;16:200–2.
77. Djuretic T, Herbert J, Drobniewski F, et al. Antibiotic resistant tuberculosis in the United Kindom: 1993–1999. Thorax 2002;57:477–82
78. Zwolska Z, Augustynowicz-Kopec E, Klatt M. Primary and acquired drug resistance in Polish tuberculosis patients: results of a study of the national drug resistance surveillance programme. Int J Tuberc Lung Dis 2000;4:832–8.
79. Ruddy M, Balabanova Y, Graham C, et al. Rates of drug resistance and risk factor analysis in civilian and prison patients with tuberculosis in Samara Region, Russia. Thorax 2005;60:130–5.
80. Schaberg T, Glober G, Reichert B, et al. Drug-resistant pulmonary tuberculosis inBerlin, Germany, 1987–1993. Eur Respir J 1995;8:1067
81. Crudu V, Arnadottir Th, Laticevschi D. Resistance to anti-tuberculosis drugs and practices in drug susceptibility testing in Moldova, 1995–1999.Int J Tuberc Lung Dis .2003;7:336–42.
82. A Faustini, A J Hall, C A Perucci.Risk factors for multidrug resistant tuberculosis in Europe: a systematic review. Thorax 2006;61:158–163.
83. D. Falzon, A. Infuso,F. A?t-Belghiti.In the European Union, TB patients from former Soviet countries have a high risk of multidrug resistance. INT J TUBERC LUNG DIS .2006;10(9):954–958
84. C. M. Clark, J. Li, C. R. Driver, S. S. Munsiff.Risk factors for drug-resistant tuberculosis among non-US-born persons in New York City. INT J TUBERC LUNG DIS 2005;9(9):964–969
85. Migliori GB, Fattorini L, Vaccarino P, et al. Prevalence of resistance to antituberculosis drugs: results of the 1998/99 national survey in Italy. Int J TubercLung Dis .2002;6:32–8.
86. Kanavaki S , Mantadakis E , Nikolaou S.et al. Antimicrobial resistance of Mycobacterium tuberculosis isolates from children in Greece, 1994-2004. Int J Tuberc Lung Dis. 2007;11(4):424-8.
87. Khalilzadeh S, Boloorsaz MR.Primary and acquired drug resistance in childhood tuberculosis.East Mediterr Health J. 2006 Nov;12(6):909-14
88. De Souza MB, Antunes CM, Garcia GF.Multidrug-resistant Mycobacterium tuberculosis at a referral center for infectious diseases in the state of Minas Gerais, Brazil: sensitivity profile and related risk factors.J Bras Pneumol. 2006 ;32(5):430-7.
89.梅建,薛桢,沈鑫等.原发性耐药是耐药结核病产生的重要原因[J].中华结核和呼吸杂志,2006:29(2):75~79
90. Diz S, López-Vélez R, Moreno A, et al.Epidemiology and clinical features of tuberculosis in immigrants at an infectious diseases department in Madrid. Int J Tuberc Lung Dis. 2007 ;11(7):769-74.
91. Valérie Schwoebel, Bénédicte Decludt, Anne-Claire de Benoist,et al.Multidrug resistant tuberculosis in France 1992-4:two case-control studies. BMJ. 1998 Sep 5;317(7159):630-1.
92. Escalante, P, S. Ramaswamy, H. Sanabria, H, et al. Genotypic characterization of drug-resistant Mycobacterium tuberculosis isolates.from Peru. Tuberc. Lung Dis. 1998;79:111–118.
93. Jun-ichiro Sekiguchi, Tohru Miyoshi-Akiyama, Ewa Augustynowicz-Kopec ,et al. Detection of Multidrug Resistance in Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY, Jan. 2007, 179–192
94. M. Caws, Phan Minh Duy,et al.Dau Quang Tho,et al.Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam. JOURNAL OF CLINICAL MICROBIOLOGY. 2007, 179–192
95. Igor Mokrousov, Olga Narvskaya, Tatiana Otten, et al.High Prevalence of katG Ser315Thr Substitution among Isoniazid Resistant Mycobacterium tuberculosis Clinical Isolates from Northwestern Russia, 1996 to 2001. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2002, 1417–1424
96. Rosilene Fressatti Cardoso, Marco Antonio Cardoso, Clarice Queico Fujimura Leite,et al. Characterization of ndh gene of isoniazid resistant and susceptible Mycobacterium tuberculosis isolates from Brazil. Mem Inst Oswaldo Cruz, Rio de Janeiro, 2007Vol. 102(1): 59-61
97. Saeed Zakerbostanabad , Leonid Petrovich Titov , Ahmad R. Bahrmand,et al.Frequency and molecular characterization of isoniazid resistance in katG region of MDR isolates from tuberculosis patients in southern endemic border of Iran. Infection, Genetics and Evolution .2008; 8: 15–19.
98. Shu-Lin Zhang , Hua Qi , Dun-Lian Qiu , et al.Genotypic Analysis of Multidrug-Resistant Mycobacterium tuberculosis Isolates Recovered From Central China. Biochemical Genetics,2007;45(3):312~319
99.程晓东,文彬,苏明权,等多重聚合酶链反应检测结核菌耐异烟肼相关基因.第四军医大学学报.2003 ;24 (9):849~851
100. Zhang Y, Heym B, Allen B, Young D et a1.The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature. 1992 , 358(6387): 591-593
101. Vilchèze C, Jacobs WR Jr.The mechanism of isoniazid killing: clarity through the scope of genetics.Annu Rev Microbiol. 2007;61:35-50.
102. He X, Alian A, Ortiz de Montellano PR.Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.Bioorg Med Chem. 2007 Nov 1;15(21):6649-58.
103. Kruh NA, Rawat R, Ruzsicska BP, Tonge PJ.Probing mechanisms of resistance to the tuberculosis drug isoniazid: Conformational changes caused by inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis.Protein Sci. 2007 ,16(8):1617-27
104. Tonge PJ, Kisker C, Slayden RA.Development of modern InhA inhibitors to combat drug resistant strains of Mycobacterium tuberculosis.Curr Top Med Chem. 2007;7(5):489-98.
105. Chen X, Ma Y, Jin Q,et al.Characterization of the katG, inhA, ahpC, kasA, and oxyR gene mutations in isoniazid-resistant and susceptible strain of Mycobacterium tuberculosis by automated DNA sequencing.Zhonghua Jie He He Hu Xi Za Zhi. 2005 Apr;28(4):250-3.
106. Barry CE , Slayden RA , Mdluli K.Mechanisms of isoniazid resistance in Mycobacterium tuberculosis.Drug Resist Updat. 1998;1(2):128-34.
107. Scarpellini P, Carrera P, Cichero P,et al.Detection of resistance to isoniazid by denaturing gradient-gel electrophoresis DNA sequencing in Mycobacterium tuberculosis clinical isolates.New Microbiol. 2003 Oct;26(4):345-51.
108. Kremer L, Dover LG, Morbidoni HR, et al.Inhibition of InhA activity, but not KasA activity, induces formation of a KasA-containing complex in mycobacteria.J Biol Chem. 2003;278(23):20547-54.
109. Mdluli K, Slayden RA, Zhu Y,et al.Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid.Science. 1998;280(5369):1607-11.
110. Kremer L, Dover LG, Morbidoni HR,et al.Inhibition of InhA activity, but not KasA activity, induces formation of a KasA-containing complex in mycobacteria.J Biol Chem. 2003;278(23):20547-54.
111. Abal AT, Ahmad S, Mokaddas E. Variations in the occurrence of the S315T mutation within the katG gene in isoniazid-resistant clinical Mycobacterium tuberculosis isolates from Kuwait. Microb Drug Resist 2002,8(2): 99-105.
112. Marttila HJ, Soini H, Eerola E et al. A Ser315Thr substitution in katG ispredominant in genetically heterogeneous multidrug-resistant Mycobacterium tuberculosis isolates originating from the St. Petersburg area in Russia. Antimicrob Agents Chemother. 1998, 42(9):2443-2445.
113. Van Soolingen D, De Haas PE, Van Doorn HR, et al. Mutations at amino acid position 3 l5 of the katG gene are associated with high-level resistance to isoniazid, other drug resistance , and successful transmission of Mycobacterium tuberculosis in the Netherlands. J Infect Dis 2000,182(6):1788一1790.
114. Sajduda A, Brzostek A, Poplawska M,et al. Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Poland. J Clin Microbiol. 2004, 42(6):2425-2431.
115. Silva M SN, Senna S G Ribeiro M O, et al. Mutations in katG, inhA, and ahpC Genes of Brazilian Isoniazid-Resistant Isolates of Mycobacterium tuberculosis. J Clin Microbiol, 2003, 41(9): 4471一4474.
116. Wojtyczka RD, Dworniczak S, Pacha J,et al.PCR-RFLP analysis of a point mutation in codons 315 and 463 of the katG gene of Mycobacterium tuberculosis isolated from patients in Silesia, Poland.Pol J Microbiol. 2004;53(2):89-93.
117. Wengenack NL, Lane BD, Hill PJ,et al.Purification and characterization of Mycobacterium tuberculosis katG, katG(S315T), and Mycobacterium bovis katG(R463L).Protein Expr Purif. 2004 Aug;36(2):232-43
118.张宗德,贾红艳,古淑香等.结核分枝杆菌kat G基因第463位密码子突变与异烟肼耐药的研究。中华结核和呼吸杂志1999 ;22(3):35~38
119. Soo-Young Kim, Yeon-Joon Park, Won-Il Kim,et al.Molecular analysis of isoniazid resistance in Mycobacterium tuberculosis isolates recovered from South Korea.Diagnostic Microbiology and Infectious Disease. 2003, 47: 497–502.
120. Florence Brossier, Nicolas Veziris, Chantal Truffot-Pernot,et al. Performance of the Genotype MTBDR Line Probe Assay for Detection of Resistance to Rifampin and Isoniazid in Strains of Mycobacterium tuberculosis with Low- and High-Level Resistance. JOURNAL OF CLINICAL MICROBIOLOGY , 2006 , 44(10): 3659–3664
121. Wilson K.Preparation of genomic DNA from bacteria.Curr Protoc Mol Biol. 2001 Nov;Chapter 2:Unit 2.4.
122. Oliveira CG, Martinez RA, Gaiotto FA.DNA extraction from bristles and quills of Chaetomys subspinosus (Rodentia: Erethizontidae) using a novel protocol.Genet Mol Res. 2007 Sep 30;6(3):657-66.
123. Wendy Somerville, Louise Thibert, Kevin Schwartzman,et al.Extraction of Mycobacterium tuberculosis DNA: a Question of Containment. JOURNAL OF CLINICAL MICROBIOLOGY, 2005, 2996–2997
124. WU Xue-qiong,LU Yang, ZHANG Jun-xian,et al.Detection of the mutations in katG315 and inhA-15 of Mycobacterium tuberculosis strains isolated from Chinese patients. Chin Med J 2006; 119 (3):230 :230-233
125. Manzour Hernando Hazbo′n, Michael Brimacombe, Miriam Bobadilla del Valle,et al.Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 2006, 50(8):2640–2649
126.金嘉琳、张文宏、翁心华等.华东地区耐药结核分枝杆菌katG基因的变异.中华传染病学杂志.2006.24(5)301~306.
127. M. Caws, Phan Minh Duy, Dau Quang Tho ,et al.Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam. JOURNAL OF CLINICAL MICROBIOLOGY, 2006, 44(7): 2333–2337 .
128. A. Nusrath Unissa, N. Selvakumar, Sujatha Narayanan, P.R,et al. Molecular analysis of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from India.. International Journal of Antimicrobial Agents . 2008, 71–75
129. H?fling CC, Pavan EM, Giampaglia CM,et al. Prevalence of katG Ser315 substitution and rpoB mutations in isoniazid-resistant Mycobacterium tuberculosis isolates from Brazil.Int J Tuberc Lung Dis. 2005;9(1):87-93
130. H?fling CC, Pavan EM, Giampaglia CM,et al. Prevalence of katG Ser315 substitution and rpoB mutations in isoniazid-resistant Mycobacterium tuberculosis isolates from Brazil.Int J Tuberc Lung Dis. 2005 Jan;9(1):87-93
131. Soo-Young Kim, Yeon-Joon Park, Won-Il Kim,et al.Molecular analysis of isoniazid resistance in Mycobacterium tuberculosis isolates recovered from South Korea.Diagnostic Microbiology and Infectious Disease. 2003, 47: 497–502.
132. Liselotte Aristimu?o , Raimond Arm , Alberto Cebollada , et al.Molecular characterisation of Mycobacterium tuberculosis isolates in the First National Survey of Anti-tuberculosis Drug Resistance from Venezuela. BMC Microbiology 2006, 6:90~112.
133. Z. FANG,C. DOIG,A. RAYNER,et al.Molecular Evidence for Heterogeneity of the Multiple-Drug-Resistant Mycobacterium tuberculosis Population in Scotland (1990 to 1997). OURNAL OF CLINICAL MICROBIOLOGY.1999, 37(4):998–1003
134. HARRI J. MARTTILA, HANNA SOINI, PENTTI HUOVINEN, AND MATTI K. VILJANEN.katG Mutations in Isoniazid-Resistant Mycobacterium tuberculosis Isolates Recovered from Finnish Patients. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1996, 2187–2189.
135. G. Tudó, J. González, R. Obama,et al.Study of resistance to anti-tuberculosis drugs in five districts of Equatorial Guinea: rates, risk factors, genotyping of gene mutations and molecular epidemiology. INT J TUBERC LUNG DIS 2004 ,8(1):15–22
136. Telenti A, Honore N, Bernasconi C,et al. Genotypic assessment of isoniazid and rifampin resistance in Mycobacterium tuberculosis: a blind study at reference laboratory level. J Clin Microbiol.1997, 35, 719–723
137. Piatek, AS, Telenti, A, Murray, MR, et al.. Genotypic analysis of Mycobacterium tuberculosis in two distinct populations using molecular beacons: implications for rapid susceptibility testing. Antimicrob Agents.Chemother .2000;44, 103–110.
138. Abate, Hoffner, S E, Thomsen, V O,et al. Characterization of isoniazid-resistant strains of Mycobacterium tuberculosis on the basis of phenotypic properties and mutations in katG. Eur J Clin Microbiol Infect Dis .2001;20:329–333.
139. Kiepiela, P, Bishop, K. S, Smith, A. N,et al.Genomic mutations in the katG, inhA and ahpC genes are useful for the prediction of isoniazid resistance in Mycobacterium tuberculosis isolates from Kwazulu Natal, South Africa. Tuber Lung Dis .2000;80:47–56.
140. Marttila HJ, Soini HE , Vyshnevskaya E, et al. A Ser315Thr substitution in katG is predominant in genetically heterogeneous multidrug-resistant Mycobacteriumtuberculosis isolates originating from the St. Petersburg area in Russia. Antimicrob Agents Chemoter. 1998, 42,2443–2445.
141. Lonnroth, K, L. M. Thuong, K. Lambregts, et al. Private tuberculosis care provision associated with poor treatment outcome: comparative study of a semi-private lung clinic and the NTP in two urban districts in Ho Chi Minh City, Vietnam. National Tuberculosis Programme.Int. J. Tuberc. Lung Dis. 2003 ,7:165–171
142. ELIF AKTAS,RIZA DURMAZ,DONG YANG,et al.Molecular Characterization of Isoniazid and Rifampin Resistance of Mycobacterium tuberculosis Clinical Isolatesfrom Malatya, Turkey. MICROBIAL DRUG RESISTANCE Volume 11, Number 2, 2005,94~99
143. Lee A. S., S. N. Othman, Y. M. Ho, and S. Y. Wong. Novel mutations within the embB gene in ethambutol-susceptible clinical isolates of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2004;48:4447–4449
144. Mokrousov, I, T. Otten, B. Vyshnevskiy, and O. Narvskaya. Detection of embB306 mutations in ethambutol-susceptible clinical isolates of Mycobacterium tuberculosis from Northwestern Russia: implications for genotypic resistance testing. J. Clin. Microbiol. 2002;40:3810–3813.
145. Beggs WH , Andrews FA.Nonspecific inhibition of ethambutol binding by Mycobacterium smegmatis1Antimicrob Agents Chemother ,1973;4 : 1152~1191
146. Deng L,Miknsova K, Robuck KG, et al.Recognition of multiple effects of ethambutol on metabolism of mycobacterial cell envelope. Antimicrob Agents Chemother .1995;39 :6942~7011
147. Kilburn JQ ,Takayama K,Armstrong EL ,et al1Effects of ethambutol on phospholipid metabolism in Mycobacterium smegmatis1Antimicrob AgentsChemother. 1981;19 :346~348
148. Silve G,Guillen PV ,Quemard A ,et al 1Ethambutol inhibition of glucose metabolism in mycobacteria : a possible target of the drug1 Antimicrob Agents Chemother .1993 ,37 :1536~1538.
149. Takayama K, Kilburn JO. Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis. Antimicrob Agents Chemother .1989 ,33 :1493~1499
150. Wolucka BA , Mcneil MR , deHoffmann E , et al1Recognition of the lipidintermediate for arabinan arabinogalactan biosynthesis and its relation to the mode of action of ethambutol on mycobacteria1. J Biol Chem.1994 ;269 :23328~23335.
151. Mikusova K, Slayden RA , Besra GS , et al1Biogenesis of the mycobacterial cell wall and the site of action of ethambutol Antimicrob. Agents Chemother.1995;39 :2484~2489.
152. Jagannath, C, V. M. Reddy, and P. R. Gangadharam. 1995. Enhancement of drug susceptibility of multi-drug resistant strains of Mycobacterium tuberculosis by ethambutol and dimethyl sulphoxide. J. Antimicrob. Chemother. 1995;35:381–390.
153. Sharma K, Gupta M, Pathak M,et al.Transcriptional control of the mycobacterial embCAB operon by PknH through a regulatory protein, EmbR, in vivo. J Bacteriol. 2006;188(8):2936-44.
154. Molle V, Reynolds RC, Alderwick LJ,et al.EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR. Biochem J. 2008;410(2):309-17.
155. Zheng X, Papavinasasundaram KG, Av-Gay Y,et al.Novel substrates of Mycobacterium tuberculosis PknH Ser/Thr kinase. Biochem Biophys Res Commun. 2007 ; 355(1):162-8.
156. H. Rinder, K. T. Mieskes, E. Tortoli.et al. Detection of embB codon 306 mutations in ethambutol resistant Mycobacterium tuberculosis directly from sputum samples: a low-cost, rapid approach. Molecular and Cellular Probes.2001,15,37–42
157. Igor Mokrousov, Tatiana Otten, Boris Vyshnevskiy,et al.Detection of embB306 Mutations in Ethambutol-Susceptible Clinical Isolates of Mycobacterium tuberculosis from Northwestern Russia: Implications for Genotypic Resistance Testing. JOURNAL OF CLINICAL MICROBIOLOGY. 2002,40(10):3810~3813.
158. Manzour Hernando Hazbon,1Miriam Bobadilla del Valle, Marta In?′rida Guerrero,et al.Role of embB Codon 306 Mutations in Mycobacterium tuberculosis Revisited: a Novel Association with Broad Drug Resistance and IS6110 Clustering Rather than Ethambutol Resistance .Antimicrobial gents and chemotherapy.2005;49(9): 3794–3802.
159. Jun-ichiro Sekiguchi, Tohru Miyoshi-Akiyama, Ewa Augustynowicz-Kopec,et al.Detection of Multidrug Resistance in Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY.2007;45(1):179–192 .
160. Ahmad S,Mokaddas E, Jaber AA, et al. Rapid detection of ethambutol-resistant Mycobacterium tuberculosis strains by PCR-RFLP targeting embB codons 306 and 497 and iniA codon 501 mutations. Mol. Cell. Probes. 2004. 18,299–306.
161. Laszlo A, Rahman M, Raviglione M, et al. Quality assurance programme for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Laboratory Network: first round of proficiency testing. Int J Tuberc Lung Dis 1997; 1: 231–238.
162. R. Johnson, A. M. Jordaan, L. Pretorius,E,et al.Ethambutol resistance testing by mutation detection. INT J TUBERC LUNG DIS. 2006,10(1):68–73.
163. Laszlo A, Rahman M, Raviglione M, et al. Quality assurance programme for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Laboratory Network: first round of proficiency testing. Int J Tuberc Lung Dis 1997; 1: 231–238.
164. S. Srivastava, A. Garg,1A. Ayyagari, et al.Nucleotide Polymorphism Associated with Ethambutol Resistance in Clinical Isolates of Mycobacterium tuberculosis.CURRENT MICROBIOLOGY . 2006,53:401–405
165. Daniela Isola, Manuela Pardinib, Francis Varaine,et al.A Pyrosequencing assay for rapid recognition of SNPs in Mycobacterium tuberculosis embB306 region.Journal of Microbiological Methods .2005,62: 113– 120
166. Sugawara I, Otomo K, Yamada H,et al.The molecular epidemiology of ethambutol-resistant Mycobacterium tuberculosis in Henan Province. Jpn J Infect Dis. 2005 ,58(6):393~395
167. J-R. Zhao, Y-J. Bai, Y. Wang, et al.Development of a pyrosequencing approach for rapid screening of rifampin, isoniazid and ethambutol-resistant Mycobacterium tuberculosis. Int J tuberclung dis.2006:328–332
168. Linda M. Parsons,Max Salfinger, Anne Clobridge,et al.Phenotypic and Molecular Characterization of Mycobacterium tuberculosis Isolates Resistant to both Isoniazid and Ethambutol. Antimicrobial gents and chemotherapy. 2005;49(6): 2218~2225
169. Srinivas V. Ramaswamy , Shu-Jun Dou , et al.Genotypic analysis of multidrug-resistant Mycobacterium tuberculosis isolates from Monterrey , Mexico.Journal of Medical Microbiology.2004;53:107~113
170. Mukaigawa J, Endoh M, Yanagawa Y,et al. Anti-drug pattern of drug-resistant Mycobacterium tuberculosis and analysis of mutation in drug-target genes.Kansenshogaku Zasshi. 2005;79(6):388~96
171. Igor Mokrousov, N. Vijaya Bhanu, Philip N. Suffys.et al.Multicenter evaluation of reverse line blot assay for detection of drug resistance in Mycobacterium tuberculosis clinical isolates.Journal of Microbiological Methods. 2004;57:323~ 335
172. Ann S. G. Lee, Siti Noor Khadijah Othman, Yu Min Ho,et al.Novel Mutations within the embB Gene in Ethambutol-Susceptible Clinical Isolates of Mycobacterium tuberculosis. Antimicrobial gents and chemotherapy. 2004;48(11):4447~4449 .
1. WHO. The world health report 2004: changing history. Geneva:World Health Organization, 2004.
2. Turrubiarte-Guillén N, Reyes-Morales H, Fernández-Cantón S, etal.Mortality due to selected causes of infectious and chronic non-transmissible diseases, from 1991 to 2004. Rev Med Inst Mex Seguro Soc. 2006;44( 1): 111-119.
3. Lopez AD, Mathers CD.Measuring the global burden of disease and epidemiological transitions: 2002-2030.Ann Trop Med Parasitol. 2006;100(5-6):481-99.
4. Farchi S, Mantovani J, Borgia P,et al.Tuberculosis incidence, hospitalisation prevalence and mortality in Lazio, Italy, 1997-2003. Int J Tuberc Lung Dis. 2008 ,12(2):193-8.
5. Cardoso EM. Multiple drug resistance: a threat for tuberculosis control[J] .Rev Panam Salud Publica, 2004 ,16(1):68-73.
6. Erik C. B?ttger and Burkhard Springer. Tuberculosis: drug resistance, fitness, and strategies for global control. Eur J Pediatr.2008,167:141–148
7. Ellen M Zager and Ruth McNerney. Multidrug-resistant tuberculosis .BMC Infectious Diseases. 2008, 8:10.
8. world Health Organization,International Union Against Tuberculosis and Lung Disease .Anti—tuberculosis drug resistance in the world :The WHO/IUATLD global project on anti—tuberculosis drug resistance surveillance. Geneva: WHO/IUATLD ,1997,1~120.
9. World Health Organization (WHO). Guidelines for surveillance of drug resistance in tuberculosis. WHO/CDS/TB/2003.320.Geneva:WHO, 2003.
10. world Health Organization,International Union Against Tuberculosis and Lung Disease. Anti—tuberculosis drug resistance in the world :The WHO/IUATLD global project on anti—tuberculosis drug resistance surveillance. Report NO.2.Prevalence and Trends. Geneva: WHO/IUATLD ,2000,1~107
11. Catherine Kyobutungi, Abdhalah Kasiira Ziraba, Alex Ezeh,et al.The burden of disease profile of residents of Nairobi's slums: Results from a Demographic Surveillance System.Population Health Metrics 2008, 6:1
12. Coimbra CE Jr and Basta PC.The burden of tuberculosis in indigenous peoples in Amazonia, Brazil.Trans R Soc Trop Med Hyg. 2007 ;101(7):635-6.
13. Dye C, Scheele S, Dolin P, et al. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. JAMA 1999; 282: 677–86.
14. Zhang Y, Heym B, Allen B, Young D et a1.The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature. 1992 ,358(6387):591-593
15. Graham S. Timmins and Vojo Deretic. Mechanisms of action of isoniazid. Molecular Microbiology .2006; 62(5): 1220–1227
16. Ng, V.H, Cox, J.S., Sousa, A.O, et al. Role of katG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Mol Microbiol .2004;52: 1291–1302.
17. Argyrou, A., Vetting, M.W, Aladegbami, B.er al. Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid. Nat Struct Mol Biol , 2006; 13:408–413.
18. Lancaster, J.R., Jr, and Gaston, B. NO and nitrosothiols:spatial confinement and free diffusion. Am J Physiol Lung Cell Mol Physiol.2004; 287: 465–466
19. Vilchèze C, Jacobs WR Jr.The mechanism of isoniazid killing: clarity through the scope of genetics.Annu Rev Microbiol. 2007;61:35-50.
20. He X, Alian A, Ortiz de Montellano PR.Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.Bioorg MedChem. 2007 Nov 1;15(21):6649-58.
21. Kruh NA, Rawat R, Ruzsicska BP, Tonge PJ.Probing mechanisms of resistance to the tuberculosis drug isoniazid: Conformational changes caused by inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis.Protein Sci. 2007 ,16(8):1617-27
22. Tonge PJ, Kisker C, Slayden RA.Development of modern InhA inhibitors to combat drug resistant strains of Mycobacterium tuberculosis.Curr Top Med Chem. 2007;7(5):489-98.
23. Chen X, Ma Y, Jin Q,et al.Characterization of the katG, inhA, ahpC, kasA, and oxyR gene mutations in isoniazid-resistant and susceptible strain of Mycobacterium tuberculosis by automated DNA sequencing.Zhonghua Jie He He Hu Xi Za Zhi. 2005 Apr;28(4):250-3.
24. Barry CE , Slayden RA , Mdluli K.Mechanisms of isoniazid resistance in Mycobacterium tuberculosis.Drug Resist Updat. 1998;1(2):128-34.
25. Scarpellini P, Carrera P, Cichero P,et al.Detection of resistance to isoniazid by denaturing gradient-gel electrophoresis DNA sequencing in Mycobacterium tuberculosis clinical isolates.New Microbiol. 2003 Oct;26(4):345-51.
26. Kremer L, Dover LG, Morbidoni HR, et al.Inhibition of InhA activity, but not KasA activity, induces formation of a KasA-containing complex in mycobacteria.J Biol Chem. 2003;278(23):20547-54.
27. Mdluli K, Slayden RA, Zhu Y,et al.Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid.Science. 1998;280(5369):1607-11
28. Saeed Zakerbostanabad , Leonid Petrovich Titov , Ahmad R. Bahrmand,et al.Frequency and molecular characterization of isoniazid resistance in katG region of MDR isolates from tuberculosis patients in southern endemic border of Iran. Infection, Genetics and Evolution .2008; 8: 15–19.
29. Maxim V. Afanas’ev1, Larisa N. Ikryannikova, Elena N. Il’ina1, et al.Molecular characteristics of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis isolates from the Russian Federation. Journal of Antimicrobial Chemotherapy .2007,59:1057–1064
30. Saeed ZAKER BOSTANABAD, Leonid P. TITOV,et al.katG mutations inisoniazid-resistant strains of Mycobacterium tuberculosis isolates from Belarusian patients. Tüberküloz ve Toraks Dergisi 2007; 55(3): 231-237
31. Mokrousov I, Narvskaya O, Otten T,et al.High prevalence of katG Ser315Thr substitution among isoniazid-resistant Mycobacterium tuberculosis clinical isolates from northwestern Russia, 1996 to 2001.Antimicrob Agents Chemother. 2002 May;46(5):1417-24.
32. Maxine Caws, Dau Quang Tho, Phan Minh Duy,et al.PCR-Restriction Fragment Length Polymorphism for Rapid, Low-Cost Identification of Isoniazid-Resistant Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY, June 2007, 45(6):1789–1793.
33. Min Zhang,1Jun Yue, Yan-ping Yang,et al.Detection of Mutations Associated with Isoniazid Resistance in Mycobacterium tuberculosis Isolates from China .JOURNAL OF CLINICAL MICROBIOLOGY, Nov. 2005,43(11): 5477–5482
34. Raphael C. Y. Chan, Mamie Hui, Edward W. C.et al.Genetic and phenotypic characterization of drug-resistant Mycobacterium tuberculosis isolates in Hong Kong. Journal of Antimicrobial Chemotherapy. 2007,59, 866–873
35. Herrera L , Valverde A , Saiz P , et al. Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis clinical strains isolated in the Philippines[J]. Int J Antimicrob Agents. 2004 ,23(6):572-6.
36. Shu-Lin Zhang , Hua Qi , Dun-Lian Qiu , et al.Genotypic Analysis of Multidrug-Resistant Mycobacterium tuberculosis Isolates Recovered From Central China. Biochemical Genetics, 2007;45(3-4):281-90.
37. H?fling CC, Pavan EM, Giampaglia CM,et al. Prevalence of katG Ser315 substitution and rpoB mutations in isoniazid-resistant Mycobacterium tuberculosis isolates from Brazil.Int J Tuberc Lung Dis. 2005 Jan;9(1):87-93
38. Soo-Young Kim, Yeon-Joon Park, Won-Il Kim,et al.Molecular analysis of isoniazid resistance in Mycobacterium tuberculosis isolates recovered from South Korea.Diagnostic Microbiology and Infectious Disease. 2003, 47: 497–502.
39. Jun-ichiro Sekiguchi, Tohru Miyoshi-Akiyama, Ewa Augustynowicz-Kopec,et al. Detection of Multidrug Resistance in Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY, 2007, 45(1): 179–192
40. Liselotte Aristimu?o , Raimond Arm , Alberto Cebollada , et al.Molecular characterisation of Mycobacterium tuberculosis isolates in the First National Survey of Anti-tuberculosis Drug Resistance from Venezuela. BMC Microbiology 2006, 6:90~112.
41. Zhang Y, GarbeuT , Young D1 Transformation with katGrestores isoniazid - sensitivity in Mycobacterium tuberculosis isolates resistant to arange of drug concentrations1 Mol Microbiol , 1994 , 8 : 521– 524.
42. Abal AT, Ahmad S, Mokaddas E. Variations in the occurrence of the S315T mutation within the katG gene in isoniazid-resistant clinical Mycobacterium tuberculosis isolates from Kuwait. Microb Drug Resist 2002,8(2): 99-105.
43. Marttila HJ, Soini H, Eerola E et al. A Ser315Thr substitution in katG is predominant in genetically heterogeneous multidrug-resistant Mycobacterium tuberculosis isolates originating from the St. Petersburg area in Russia. Antimicrob Agents Chemother. 1998, 42(9):2443-2445.
44. Van Soolingen D, De Haas PE, Van Doorn HR, et al. Mutations at amino acid position 3 l5 of the katG gene are associated with high-level resistance to isoniazid, other drug resistance , and successful transmission of Mycobacterium tuberculosis in the Netherlands. J Infect Dis 2000,182(6):1788一1790.
45. Sajduda A, Brzostek A, Poplawska M,et al. Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Poland. J Clin Microbiol. 2004, 42(6):2425-2431.
46. Silva M SN, Senna S G Ribeiro M O, et al. Mutations in katG, inhA, and ahpC Genes of Brazilian Isoniazid-Resistant Isolates of Mycobacterium tuberculosis. J Clin Microbiol, 2003, 41(9): 4471一4474.
47. Wojtyczka RD, Dworniczak S, Pacha J,et al.PCR-RFLP analysis of a point mutation in codons 315 and 463 of the katG gene of Mycobacterium tuberculosis isolated from patients in Silesia, Poland.Pol J Microbiol. 2004;53(2):89-93.
48. Wengenack NL, Lane BD, Hill PJ,et al.Purification and characterization of Mycobacterium tuberculosis katG , katG(S315T) , and Mycobacterium bovis katG(R463L).Protein Expr Purif. 2004 Aug;36(2):232-43
49.张宗德,贾红艳,古淑香等.结核分枝杆菌kat G基因第463位密码子突变与异烟肼耐药的研究。中华结核和呼吸杂志1999 ;22(3):35~38
50. Maxim V. Afanas’ev1, Larisa N. Ikryannikova, Elena N. Il’ina1, et al.Molecular characteristics of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis isolates from the Russian Federation. Journal of Antimicrobial Chemotherapy .2007,59:1057–1064.
51. Z. FANG,C. DOIG,.A. RAYNER,et al.Molecular Evidence for Heterogeneity of the Multiple-Drug-Resistant Mycobacterium tuberculosis Population in Scotland (1990 to 1997). OURNAL OF CLINICAL MICROBIOLOGY.1999, 37(4):998–1003
52. HARRI J. MARTTILA, HANNA SOINI, PENTTI HUOVINEN, AND MATTI K. VILJANEN.katG Mutations in Isoniazid-Resistant Mycobacterium tuberculosis Isolates Recovered from Finnish Patients. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1996, 2187–2189.
53.金嘉琳、张文宏、翁心华等.华东地区耐药结核分枝杆菌katG基因的变异.中华传染病学杂志.2006.24(5)301~306.
54. WU Xue-qiong,LU Yang, ZHANG Jun-xian,et al.Detection of the mutations in katG315 and inhA-15 of Mycobacterium tuberculosis strains isolated from Chinese patients. Chin Med J 2006; 119 (3):230 :230-233
55. JIAO Wei-wei, Mokrousov Igor, SUN Gui-zhi, et al.Molecular characteristics of rifampin and isoniazid resistant Mycobacterium tuberculosis strains from Beijing, China. Chin Med J 2007;120(814 9):814-819
56.王海英,刘志敏,郑建礼等.结核杆菌异烟肼表型耐药与katG基因突变相关性研究.齐鲁医学检验2005 ,16 (5 ):31~35
57. JIAO Wei-wei, Mokrousov Igor, SUN Gui-zhi, et al.Molecular characteristics of rifampin and isoniazid resistant Mycobacterium tuberculosis strains from Beijing, China. Chin Med J 2007;120(814 9):814-819.
58. Xin Ma, Haiying Wang, Yunfeng Deng,et al.rpoB Gene Mutations and Molecular Characterization of Rifampin-Resistant Mycobacterium tuberculosis Isolates from Shandong Province, China. JOURNAL OF CLINICAL MICROBIOLOGY, Sept. 2006, 44, 3409–3412
59. Saeed ZAKER BOSTANABAD , Ahmadreza BAHRMAND , Leonid Pet al.Identification of mutations in the rpoB encoding the RNA polymerase beta subunitin rifampicine-resistant Mycobacterium tuberculosis strains from Iran. Tüberküloz ve Toraks Dergisi 2007; 55(4): 370-377.
60. M. Caws, Phan M D,Dau Quang Tho,et al.Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam. JOURNAL OF CLINICAL MICROBIOLOGY.2006;44:2333–2337
61. Valim AR,Rossetti ML,Ribeiro MO,et al.Mutations in the rpoB gene of multidrug resisitant Mycobacterium tuberculosis isolates from Brazil[J].J Clin Microbiol. 2000,38:3119～3122.
62. Ahmad S, Mokaddas E,Farees E. Characterization of rpoB mutation in rifampin resisitant clinical Mycobacterium tuberculosis isolates from Kuwait and Dubai[J]. Diagn Microbiol Infect Dis, 2002,44(3):245~250
63. Ahmad S, Mokaddas E,Farees E. Characterization of rpoB mutation in rifampin resisitant clinical Mycobacterium tuberculosis isolates from Kuwait and Dubai[J]. Diagn Microbiol Infect Dis, 2002,44(3):245~250
64. Sajduda A, Brzostek A, Poplawska M, et al. Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Poland[J]. J Clin Microbiol. 2004 ,42(6):2425-31.
65. Tesic J, Lepsanovic Z, Mirovic V. Evaluation of usefulness of single-strand conformation polymorphism method for rapid detection of rifampicin-resistant Mycobacterium tuberculosis[J]. Vojnosanit Pregl. 2004 ,61(2):169-72.
66.葛超荣,林瑞炮,陈智等.结核分枝杆菌耐多药性与rpoB及katG基因关系的初步研究[J].中华结核和呼吸杂志.2003;26(4):245~249
67. Sajduda A, Brzostek A, Poplawska M, et al. Molecular characterization of rifampin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Poland[J]. J Clin Microbiol. 2004;42(6):2425-31.
68. Ruiru Shi , Jianyuan Zhang , Chuanyou Li , et al.Detection of streptomycin resistance in Mycobacterium tuberculosis clinical isolates from China as determined by denaturing HPLC analysis and DNA sequencing. Microbes and Infection .2007;9:1538~1544.
69. T. Hosaka, J. Xu, K. Ochi, Increased expression of ribosome recycling factor is responsible for the enhanced protein synthesis during the late growth phase in anantibiotic-overproducing Streptomyces coelicolor ribosomal rpsL mutant, Mol. Microbiol. 2006;61: 883~897.
70. A. Brzostek, A. Sajduda, T. Sliwinski, et al.Molecular characterization of streptomycin-resistant Mycobacterium tuberculosis strains isolated in Poland,Int. J. Tuberc. Lung Dis. 8 (2004) 1032e1035.
71. Sharma D, Cukras AR, Rogers EJ, et al.Mutational analysis of S12 protein and implications for the accuracy of decoding by the ribosome.J Mol Biol. 2007;374(4):1065-76.
72. Tracevska T, Jansone I, Nodieva A et al.Characterisation of rpsL, rrs and embB mutations associated with streptomycin and ethambutol resistance in Mycobacterium tuberculosis[J]. Res Microbiol. 2004 ,55(10):830-834.
73. Springer B, Kidan YG, Prammanan T, et al. Mechanisms of streptomycin resistance: selection of mutations in the 16SrRNA gene conferring resistance[J]. Antimicrob Agents Chemother.2001,45(10):2877-2884.
74. Brzostek A, Sajduda A, Sliwinski T, et al. Molecular characterisation of streptomycin-resistant Mycobacterium tuberculosis strains isolated in Poland[J]. Int J Tuberc Lung Dis. 2004 ,8(8):1032-1035.
75. Lee AS, Tang LL, Lim IH, et al. Characterization of pyrazinamide and of loxacin resistance among drug resistanct Mycobacterium tuberculosis isolates from Singapore[J]. Int J infect Dis , 2002,6(1):48-51.
76. Miyagi C, Yamane N, Yogesh B, et al.Genetic and phenotypic characterization of pyrazinamide-resistant mycobacterium tuberculosis complex isolates in Japan[J]. Diagn Microbiol Infect Dis. 2004 ,48(2):111-6.
77. Endoh T, Yagihashi A, Uehara N, Kobayashi D, Pyrazinamide resistance associated with pncA gene mutation in Mycobacterium tuberculosis in Japan[J]. Epidemiol Infect. 2002 ,128(2):337-42.
78. Scorpio A, Lindholm LP, Heifetes L, et al.Characterization of pncA mutations in pyrazinamide resistant Mycobacterium tuberculosis[J]. Antimicrob Agenta Chemother, 1997,41(3):540-543.
79. Telenti A, Philipp WJ, Sreevatsan S, et al. The emb operon,a gene cluster of Mycobacteriumtuberculosis involved in resistance to ethambutol. Nature Medicine,1997, 3(5):567-570
80. Sreevatsan S, Stockbauer KE, Xi P, et al. Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations. Antimicrob. Agents Chemother., 1997,41(8):1677-1681
81. Ramaswamys S, Amin Aq Goksel S, et al. Molecular genetic analysis of nucleotide polymorphisms associated with ethambutol resistance in human isolates of Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2000, 44(2):326-336
82. Hazbon MH, Bobadilla del Valle M, Guerrero MI, et al. Role of embB codon 306 mutations inMycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than etnambutol resistance. Antimicrob Agents Chemothe.r, 2005,49(9):3794-3802
83. Belanger AE, Besra GS, Ford ME, et al. The embAB genes of Mycobacterium avium encode an arabinosyl transferase involed in cell wall arabinan biosynthesis that is the target for the antimycobacterial ethambutol. Proc Natl Acad Sci USA, 1996, 93(21):11919-11924.
84. Mikusova K, Slayden RA , Besra GS , et al1Biogenesis of the mycobacterial cell wall and the site of action of ethambutol1 Antimicrob Agents Chemother ,1995 ,39 :2484~2489
85. Deng, L, Mikusova, K, Robuck, KG, et al. Recognition of multiple effectsof ethambutol on metabolism of mycobacterial cell envelope .Antimicrob. Agents Chemother. 1995: 39: 694–701.
86. Claudia Plinke, Sabine Ru¨sch-Gerdes, and Stefan Niemann. Significance of Mutations in embB Codon 306 for Prediction of Ethambutol Resistance in Clinical Mycobacterium tuberculosis Isolates. Antimicrobial gents and chemotherapy .2006; 37(2):1900–1902
87. Xin Shen, Guo-miao Shen, Jie Wu,et al.Association between embB Codon 306 Mutations and Drug Resistance in Mycobacterium tuberculosis. Antimicroboal Agnts and chemotherapy. 2007;51(7):. 2618–2620
88. Hazbon, M. H, M. Bobadilla del Valle, M. I. Guerrero, et al. Role of embB codon
306 mutations in Mycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than ethambutol resistance.AntimicrobAgents Chemother. 2005.49:3794–3802.
89. S. Ahmad, A. A. Jaber, E. Mokaddas.Frequency of embB codon 306 mutations in ethambutol-susceptible and -resistant clinical Mycobacterium tuberculosis isolates in Kuwait.Tuberculosis .2007; 87:123–129.
90. Escuyer, V. E, M. A. Lety, J. B. Torrelles, K. H,et al.The role of the embA and embB gene products in the biosynthesis of the terminal hexaarabinofuranosyl motif of Mycobacterium smegmatis arabinogalactan.J. Biol. Chem. 2001.276:48854–48862.
91. Jagannath, C, V. M. Reddy, and P. R. Gangadharam. 1995. Enhancement of drug susceptibility of multi-drug resistant strains of Mycobacterium tuberculosis by ethambutol and dimethyl sulphoxide. J. Antimicrob. Chemother. 1995.35:381–39
92.严碧涯主编结核病学北京出版社2003第1版
93. Rindi L, Lari N, Bonanni D,et al. Detection of Mycobacterium tuberculosis genotypic groups by a duplex real-time PCR targeting the katG and gyrA genes[J]. J Microbiol Methods. 2004 ,59(2):283-7
94. Post FA, Willcox PA, Mathema B,et al. Genetic polymorphism in Mycobacterium tuberculosis isolates from patients with chronic multidrug-resistant tuberculosis[J]. J Infect Dis. 2004 ,190(1):99-106
95. Ramaswamy SV, Dou SJ, Rendon A. Genotypic analysis of multidrug-resistant Mycobacterium tuberculosis isolates from Monterrey, Mexico[J]. J Med Microbiol. 2004 ,53(2):107-113
96.梁建琴.吴雪琼.曹立雪,等.应用膜反向斑点杂交技术快速检测结核分枝杆菌耐乙胺丁醇基因型的研究[J].微生物学报,2004,44(2):215～219
97. Yoshikawa Y, Ichihara T, Suzuki Y .Detection of drug-resistant Mycobacterium tuberculosis isolates using DNA microarray[J]. Rinsho Biseibutshu Jinsoku Shindan Kenkyukai Shi. 2003,14(1):45-50.
98. World Health Organisation: Anti-tuberculosis drug resistance in the world: Report Number 3. The WHO/IUALTD global project on anti-tuberculosis drug resistance surveillance. In: WHO/CDS/TB/2004.343. Geneva: WHO; 2004.(http://www.who.int/tb/publications/who_htm_tb_2004_343/en/index.html
99. World Health Organization. Anti-tuberculosis drug resistance in the world. Fourth global report. Geneva , Switzerland: World Health Organization; 2008.http://www.who.int/tb/publications/2008/drs_report4_26feb08.pdf
100.刘宇红,姜广路,赵立平等.第四次全国结核病流行病学抽样调查—结核分枝杆菌耐药性分析与评价[J].中华结核和呼吸杂志.2002;25 (4):224~227
101. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998; 393(6685):537-544.
102. Finken M, Kirschner只Meier A, et al. Molecular basis of streptomycin resistance in Mycobacterium tuberculosis: alterations of the ribosomal protein S12 gene and point mutations within a functional 16S ribosomal pseudolcnot. Mol Microbiol.1993;9(6):1239-1246.
103. Zhang Y. Telenti A. Genetics of drug resistance in Mycobacterium tuberculosis.Hatfull G. Jacobs W R, Molecular genetics of mycobacteria [M],Washington D. C:AMS Press. 2000:35
104. Ainsa J A, Martin C, Gicquel B, et al. Gomz一Lus. Characterization of the chromosomal aminoglycoside 2’-N-acetyltrans-ferase gene from Mycobacterium fortuitium[J].Antimicrob Agents Chemother. 1996;40:2350
105. Zhang Y.Mitchison D. The curious characteristics of pyrazinamide:a review [J].Int J Tuberc Lung Dis. 2003; 7:6
106. Zhang H, Deng JY, Bi LJ,et al.Characterization of Mycobacterium tuberculosis nicotinamidase/pyrazinamidase. FEBS J. 2008 ;275(4):753-62.
107. Chan RC, Hui M, Chan EW,et al.Genetic and phenotypic characterization of drug-resistant Mycobacterium tuberculosis isolates in Hong Kong. J Antimicrob Chemother. 2007 ;59(5):866-73.
108. Somoskovi A, Dormandy J, Parsons LM,et al.Sequencing of the pncA gene in members of the Mycobacterium tuberculosis complex has important diagnostic applications: Identification of a species-specific pncA mutation in "Mycobacterium canettii" and the reliable and rapid predictor of pyrazinamide resistance. J Clin Microbiol. 2007;45(2):595-9.
109. Barco P, Cardoso RF, Hirata RD,et al.pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis clinical isolates from the southeast region of Brazil. J Antimicrob Chemother. 2006;58(5):930-5.
110. Denkin S, Volokhov D, Chizhikov V,et al.Microarray-based pncA genotyping ofpyrazinamide-resistant strains of Mycobacterium tuberculosis. J Med Microbiol. 2005 ;54(12):1127-31
111. Morris S,Bai GH,Suffys P,et al. Moleculars mechanisms of multiple drug resistance in clinical isolates of Mycobacterium tuberculosis. J Infect Dis,1995;171:954一960.
112.庄玉辉.结核分枝杆菌耐药性分子机理研究若干进展.中华结核和呼吸杂志.1997;20(6):329一331.
113.胡忠义,靳安佳,景奉香,等.结核分枝杆菌耐多药的基因研究.中华检验医学杂志. 2001;24(20):73~75
114.吴雪琼,庄玉辉,张俊仙,等.耐多药结核病耐药分子机制的研究.中华结核和呼吸杂志.1997;20:332一335.
115. Jun-ichiro Sekiguchi, Tohru Miyoshi-Akiyama, Ewa Augustynowicz-Kopec,et al.Detection of Multidrug Resistance in Mycobacterium tuberculosis. JOURNAL OF CLINICAL MICROBIOLOGY.. 2007;179–192.
116. Lipin MY, Stepanshina VN,Shemyakin IG, et al.Association of specific mutations in katG , rpoB , rpsL and rrs genes with spoligotypes of multidrug-resistant Mycobacterium tuberculosis isolates in Russia. Clin Microbiol Infect. 2007;13(6):620-626.
117. Davies J,Davis D D. Misreading of ribonucleic acid code words induced by aminoglycoside antibiotics. The effect of drug concentration[J].J Bio1 Chem, 1968, 243:3312
118. Garvin R T.Biswas U K , Gorini L.Che effects of streptomycin or dihydrostreptomycin binding to 16S rRNA or to 30S ribosomal subunits[J].Proc Nail Acad Sci USA,1974,71:3814