耐阿奇霉素淋球菌的基因分型研究及头孢曲松低敏淋球菌的penA、porB、mtrR基因多态性研究
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摘要
淋病奈瑟菌(简称淋球菌)是淋病的病原体,可引起尿道炎、宫颈炎等。阿奇霉素是我国尿道炎、宫颈炎常用治疗药物之一,临床症状不典型的淋病患者可能只接受到阿奇霉素治疗,故开展淋球菌对阿奇霉素的敏感性监测是非常有意义的。与阿奇霉素不同,头孢曲松作为目前淋病一线治疗药物,一直是我国淋球菌耐药监测药物之一,监测结果显示近年来淋球菌对头孢曲松的敏感性下降趋势比较明显,故开展淋球菌对头孢曲松的耐药机制研究显得越来越重要。淋球菌多抗原序列分型方法(NG-MAST)是一种操作简便、分型能力强的基因分型方法,本研究应用NG-MAST方法分析耐阿奇霉素淋球菌和头孢曲松低敏株的基因型别和菌株间的进化关系,为淋病防治工作提供参考依据。全文分为3个部分,各部分的主要内容简述如下：
第一部分南京和重庆地区淋球菌对阿奇霉素的敏感性测定
本部分旨在了解南京和重庆地区淋球菌对阿奇霉素的敏感性。选取2008年及2009年南京和重庆地区分离的318株淋球菌,采用琼脂稀释法测定阿奇霉素、头孢曲松、大观霉素、四环素、环丙沙星对这318株淋球菌的最低抑菌浓度(MIC),耐阿奇霉素淋球菌定义为每批实验中大于或等于阿奇霉素对质控菌株WHO P(阿奇霉素耐药株)的MIC值的菌株。318株淋球菌中有17株(5.3%)淋球菌对阿奇霉素耐药。
第二部分耐阿奇霉素淋球菌的NG-MAST基因分型研究
本部分旨在了解南京和重庆地区耐阿奇霉素淋球菌的基因型别和菌株间的进化关系。对第一部分检测出的17株耐阿奇霉素淋球菌进行NG-MAST基因分型,并利用Mega软件作进化树分析。17株耐阿奇霉素淋球菌共有11种NG-MAST基因型别,其中5种为新注册的基因型别。有6株菌的基因型别(ST)为ST3356,2株高度耐阿奇霉素的菌株(MIC>64mg/L)具有相同的基因型别ST1866。基因型别ST3367及4种新注册的基因型别与菌株数最多的基因型别ST3356亲缘关系较近,可能均为短传播链上同一来源菌株。
第三部分头孢曲松低敏淋球菌的penA、porB、mtrR基因多态性研究
本部分旨在了解penA、porB、mtrR基因多态性在淋球菌对头孢曲松敏感性下降中的作用。选取第一部分检测出的17株头孢曲松低敏株和4株头孢曲松敏感株进行penA、porB、mtrR基因测序和NG-MAST基因分型。21株淋球菌的penA基因编码的青霉素结合蛋白2(PBP2)中共发现9种氨基酸结构模式,其中2种未报道过。有8株头孢曲松低敏株中存在ⅩⅧ型PBP2,有4株头孢曲松低敏株中存在ⅩⅢ型PBP2,未发现镶嵌状结构模式(X)PBP2。有18株淋球菌含有porB1b基因(编码PorB1b蛋白),PorB1b中I218M、M257T/M257R和G259V氨基酸置换都只在头孢曲松低敏株中出现。21株淋球菌的1mtrR基因编码的MtrR中存在A39T或G45D或H105Y氨基酸置换,A39T氨基酸置换只在3株头孢曲松低敏株中出现,G45D或H105Y氨基酸置换在头孢曲松低敏株和头孢曲松敏感株中均出现。17株头孢曲松低敏株共有13种NG-MAST基因型别,其中3种为新注册的基因型别。PENa、porB、mtrR基因多态性可能在淋球菌对头孢曲松敏感性下降中起一定作用。
Neisseria gonorrhoeae (NG) is the causative pathogen of gonorrhea, which causes both symptomatic and asymptomatic infections. Increasing antimicrobial resistance in NG is a major challenge for prevention and control of gonorrhea. Azithromycin is usually used for the treatment of urethritis and cervicitis in syndromic management, so azithromycin-resistant NG strains should be monitored in China. Although the recommended first-line treatment for gonorrhea in China is ceftriaxone or spectinomycin, in recent years, the emergence and spread of NG strains with reduced susceptibility to ceftriaxone (Cef) has been reported in China. It's essential to monitor the susceptibility to ceftriaxone of NG strains and launch research on the resistance mechanism of NG strains resistant or non-susceptible to ceftriaxone. NG multiantigen sequence typing (NG-MAST) is a discriminatory genotyping method and easy for performing. In the current study, NG-MAST method was used to investigate the genotypes of azithromycin-resistant NG isolates and Cef isolates. The current study was divided into three parts as follow:
Chapter1. Resistance to azithromycin of NG isolates from Nanjing and Chongqing
We aimed to investigate azithromycin susceptibility in NG from Nanjing and Chongqing. NG isolates (n=318) were cultured from Nanjing and Chongqing between2008and2009. Minimum inhibitory concentration (MIC) of azithromycin, ceftriaxone, spectinomycin, tetracycline, and ciprofloxacin was determined using the agar dilution method. Azithromycin-resistant isolates were defined as having an MIC value equal to or greater than that of strain WHO P, which is internationally recognized as azithromycin-resistant (MIC=2mg/L). Seventeen (5.3%) isolates showed resistance to azithromycin. A relatively high prevalence of azithromycin-resistant NG strains implies that azithromycin should not be recommended for the treatment of gonococcal urethritis or cervicitis in Nanjing and Chongqing.
Chapter2. Genotyping of azithromycin-resistant NG isolates by NG-MAST method
Our objective was to investigate the genotypes of azithromycin-resistant NG isolates from Nanjing and Chongqing. Seventeen azithromycin-resistant NG isolates identified in Chapter1were genotyped by NG-MAST method and analyzed using Mega software to construct the phylogenetic tree. Among these isolates (n=17),11sequence types were identified by NG-MAST method, of which5were novel. The most common sequence type (ST) was ST3356, represented by6isolates. ST1866was represented by2isolates, which were isolated from patients with an unknown relationship, and both isolates were highly resistant to azithromycin, i.e., displayed an MIC of>64mg/L. In the phylogenetic analysis, the isolates of4novel STs and1known ST clustered closely to the ST3356isolates and, accordingly, these may all have a common ancestor.
Chapter3. Genetic polymorphisms in penA, porB and mtrR genes of Cef1isolates
Our aim was to investigate the correlation of different polymorphisms in the penA, porB, and mtrR genes of Cef isolates. Seventeen Cef isolates and4susceptible NG isolates were characterized by NG-MAST method and sequencing of penA, porB, and mtrR alleles. Among the21NG isolates,9mutation patterns were observed in penicillin-binding protein2(PBP2), encoded by penA gene, of which2were novel. The most common mutation pattern is XVIII, represented by8Cef isolates. And mutation pattern XIII was represented by4Cef isolates. None of the21NG isolates contained a mosaic PBP2(pattern X). Eighteen of the21NG isolates had a porBlb gene, encoding porin protein PorBlb. Substitutions of I218M/M257T/G259V were present in PorBlb of4Cef isolates, and another257substitution (M257R) were present in PorBlb of6Cef isolates. Substitution of A39T was observed in MtrR, encoded by mtrR gene, of3Cef isolates. Substitutions of G45D or H105Y were observed in MtrR, encoded by mtrR gene, of both Cef and susceptible isolates. All17Cef isolates were assigned13NG-MAST sequence types, of which3were novel. In conclusion, these mutations in penA, porB and mtrR genes may play a role for the reduced susceptibility to ceftriaxone in NG
第一部分南京和重庆地区淋球菌对阿奇霉素的敏感性测定
本部分旨在了解南京和重庆地区淋球菌对阿奇霉素的敏感性。选取2008年及2009年南京和重庆地区分离的318株淋球菌,采用琼脂稀释法测定阿奇霉素、头孢曲松、大观霉素、四环素、环丙沙星对这318株淋球菌的最低抑菌浓度(MIC),耐阿奇霉素淋球菌定义为每批实验中大于或等于阿奇霉素对质控菌株WHO P(阿奇霉素耐药株)的MIC值的菌株。318株淋球菌中有17株(5.3%)淋球菌对阿奇霉素耐药。
第二部分耐阿奇霉素淋球菌的NG-MAST基因分型研究
本部分旨在了解南京和重庆地区耐阿奇霉素淋球菌的基因型别和菌株间的进化关系。对第一部分检测出的17株耐阿奇霉素淋球菌进行NG-MAST基因分型,并利用Mega软件作进化树分析。17株耐阿奇霉素淋球菌共有11种NG-MAST基因型别,其中5种为新注册的基因型别。有6株菌的基因型别(ST)为ST3356,2株高度耐阿奇霉素的菌株(MIC>64mg/L)具有相同的基因型别ST1866。基因型别ST3367及4种新注册的基因型别与菌株数最多的基因型别ST3356亲缘关系较近,可能均为短传播链上同一来源菌株。
第三部分头孢曲松低敏淋球菌的penA、porB、mtrR基因多态性研究
本部分旨在了解penA、porB、mtrR基因多态性在淋球菌对头孢曲松敏感性下降中的作用。选取第一部分检测出的17株头孢曲松低敏株和4株头孢曲松敏感株进行penA、porB、mtrR基因测序和NG-MAST基因分型。21株淋球菌的penA基因编码的青霉素结合蛋白2(PBP2)中共发现9种氨基酸结构模式,其中2种未报道过。有8株头孢曲松低敏株中存在ⅩⅧ型PBP2,有4株头孢曲松低敏株中存在ⅩⅢ型PBP2,未发现镶嵌状结构模式(X)PBP2。有18株淋球菌含有porB1b基因(编码PorB1b蛋白),PorB1b中I218M、M257T/M257R和G259V氨基酸置换都只在头孢曲松低敏株中出现。21株淋球菌的1mtrR基因编码的MtrR中存在A39T或G45D或H105Y氨基酸置换,A39T氨基酸置换只在3株头孢曲松低敏株中出现,G45D或H105Y氨基酸置换在头孢曲松低敏株和头孢曲松敏感株中均出现。17株头孢曲松低敏株共有13种NG-MAST基因型别,其中3种为新注册的基因型别。PENa、porB、mtrR基因多态性可能在淋球菌对头孢曲松敏感性下降中起一定作用。
Neisseria gonorrhoeae (NG) is the causative pathogen of gonorrhea, which causes both symptomatic and asymptomatic infections. Increasing antimicrobial resistance in NG is a major challenge for prevention and control of gonorrhea. Azithromycin is usually used for the treatment of urethritis and cervicitis in syndromic management, so azithromycin-resistant NG strains should be monitored in China. Although the recommended first-line treatment for gonorrhea in China is ceftriaxone or spectinomycin, in recent years, the emergence and spread of NG strains with reduced susceptibility to ceftriaxone (Cef) has been reported in China. It's essential to monitor the susceptibility to ceftriaxone of NG strains and launch research on the resistance mechanism of NG strains resistant or non-susceptible to ceftriaxone. NG multiantigen sequence typing (NG-MAST) is a discriminatory genotyping method and easy for performing. In the current study, NG-MAST method was used to investigate the genotypes of azithromycin-resistant NG isolates and Cef isolates. The current study was divided into three parts as follow:
Chapter1. Resistance to azithromycin of NG isolates from Nanjing and Chongqing
We aimed to investigate azithromycin susceptibility in NG from Nanjing and Chongqing. NG isolates (n=318) were cultured from Nanjing and Chongqing between2008and2009. Minimum inhibitory concentration (MIC) of azithromycin, ceftriaxone, spectinomycin, tetracycline, and ciprofloxacin was determined using the agar dilution method. Azithromycin-resistant isolates were defined as having an MIC value equal to or greater than that of strain WHO P, which is internationally recognized as azithromycin-resistant (MIC=2mg/L). Seventeen (5.3%) isolates showed resistance to azithromycin. A relatively high prevalence of azithromycin-resistant NG strains implies that azithromycin should not be recommended for the treatment of gonococcal urethritis or cervicitis in Nanjing and Chongqing.
Chapter2. Genotyping of azithromycin-resistant NG isolates by NG-MAST method
Our objective was to investigate the genotypes of azithromycin-resistant NG isolates from Nanjing and Chongqing. Seventeen azithromycin-resistant NG isolates identified in Chapter1were genotyped by NG-MAST method and analyzed using Mega software to construct the phylogenetic tree. Among these isolates (n=17),11sequence types were identified by NG-MAST method, of which5were novel. The most common sequence type (ST) was ST3356, represented by6isolates. ST1866was represented by2isolates, which were isolated from patients with an unknown relationship, and both isolates were highly resistant to azithromycin, i.e., displayed an MIC of>64mg/L. In the phylogenetic analysis, the isolates of4novel STs and1known ST clustered closely to the ST3356isolates and, accordingly, these may all have a common ancestor.
Chapter3. Genetic polymorphisms in penA, porB and mtrR genes of Cef1isolates
Our aim was to investigate the correlation of different polymorphisms in the penA, porB, and mtrR genes of Cef isolates. Seventeen Cef isolates and4susceptible NG isolates were characterized by NG-MAST method and sequencing of penA, porB, and mtrR alleles. Among the21NG isolates,9mutation patterns were observed in penicillin-binding protein2(PBP2), encoded by penA gene, of which2were novel. The most common mutation pattern is XVIII, represented by8Cef isolates. And mutation pattern XIII was represented by4Cef isolates. None of the21NG isolates contained a mosaic PBP2(pattern X). Eighteen of the21NG isolates had a porBlb gene, encoding porin protein PorBlb. Substitutions of I218M/M257T/G259V were present in PorBlb of4Cef isolates, and another257substitution (M257R) were present in PorBlb of6Cef isolates. Substitution of A39T was observed in MtrR, encoded by mtrR gene, of3Cef isolates. Substitutions of G45D or H105Y were observed in MtrR, encoded by mtrR gene, of both Cef and susceptible isolates. All17Cef isolates were assigned13NG-MAST sequence types, of which3were novel. In conclusion, these mutations in penA, porB and mtrR genes may play a role for the reduced susceptibility to ceftriaxone in NG
引文
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