大肠杆菌质粒介导喹诺酮耐药机制研究
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摘要
随着喹诺酮类抗生素在临床上的广泛应用，大肠杆菌对其耐药性也日益严重。以往的研究发现，大肠杆菌对喹诺酮类的耐药主要由靶位改变和主动外排所致，两者均由染色体介导。随后发现质粒介导的喹诺酮耐药是其耐药性传播的主要途径。目前国内外对大肠杆菌喹诺酮类耐药机制的研究多集中于人类临床分离株，食源性分离株的研究较少。本论文以食源性和临床分离的大肠杆菌为研究对象，对分离株的耐药性以及I类整合子携带情况进行检测分析，深入探讨大肠杆菌对喹诺酮类药物的耐药机制，旨在了解不同来源大肠杆菌中相关耐药基因的分布及水平传播，并寻找有效的方法切断其传播途径，以遏制大肠杆菌耐药性的进一步扩散。研究所得结论如下：
（1）对33株分离自熟肉制品的食源性大肠杆菌和66株临床大肠杆菌分离株的药敏试验结果显示，菌株对磺胺甲基异噁唑、复方新诺明、氨苄西林、四环素和链霉素耐药最为严重，对阿米卡星和氯霉素的敏感性最好。食源性菌株中耐受3种或3种以上抗生素的多重耐药菌株有18株（54.5%）；临床分离株中多重耐药情况相对严重，所有菌株均对3种或3种以上抗生素具有耐药性，其中有将近一半的菌株耐10种或10种以上抗生素，有2株大肠杆菌对所用的14种抗生素全部显示出耐药性。
（2）食源性和临床分离的大肠杆菌中I类整合子的阳性率分别为18.2%和54.5%。I类整合子阳性的食源性菌株携带3种不同类型的基因盒，分别为dfrA17-aadA5，dfrA1-aadA1和dfrA12-orfF-aadA2。I类整合子阳性的临床分离株携带7种不同类型的基因盒，分别为dfrA17-aadA5，dfrA12-orfF-aadA2，dfr2d，aacA4-catB8-aadA1，aadA2+dfrA12-orfF-aadA2，dfrA5，dfr2d+dfrA17-aadA5。
（3）食品分离株中未检出qnr基因，而临床分离株中qnr基因阳性共7株，其中2株携带qnrA1，5株携带qnrS1。临床株中aac(6’)-Ib基因阳性菌株共有20株，其中11株经确认为携带其变体基因aac(6’)-Ib-cr。5株qnr阳性菌株通过接合转移成功的将耐药质粒转入受体菌E. coli J53中，接合效率分别在3.4×10~(-5)到2.4×10~(-3)之间。供体菌对喹诺酮类耐药水平明显高于其接合子。通过对供体菌、接合子和受体菌的QRDRs检测发现，5株供体菌均在GyrA亚基和/或ParC亚基存在氨基酸突变，其相应的接合子及受体菌J53的QRDRs均未发现突变。这说明染色体突变介导了较高水平的喹诺酮耐药；qnr基因的单独存在可使菌株对喹诺酮类药物的敏感性降低，从而介导了低水平的耐药。相对于受体菌来说，接合子对环丙沙星和左氧氟沙星的MIC值分别增加了32～128倍和16～32倍，对庆大霉素、阿米卡星、头孢他啶、头孢哌酮、头孢吡肟、氨苄西林和磺胺甲基异噁唑的耐药性也有大幅提高。
（4）通过实时荧光定量PCR发现，筛选出的三株qnrS阳性接合子对环丙沙星的MIC值有所不同，但是qnrS基因的表达水平却基本相同。在环丙沙星和左氧氟沙星的作用下，qnrS的表达水平显著升高。结果表明qnrS基因的表达水平与喹诺酮类耐药程度有关。
（5）5株qnr阳性菌株经SDS-高温高浓度双重处理交替培养法处理后，有3株成功的筛选出了消除子，消除率在60.4%到70.8%之间。这3株菌在质粒消除后质粒图谱发生了明显变化，并且经PCR扩增反应未检出qnr基因。质粒消除后，这3株菌的耐药谱也发生了变化，对庆大霉素、阿米卡星、头孢他啶、头孢哌酮、头孢吡肟、氨苄西林和磺胺甲基异噁唑的耐药性发生了逆转，由原本的耐药变为敏感。而未成功消除耐药质粒菌株的耐药谱则没有发生变化。
As quinolones used widely in clinical medicine, the increasing prevalence of resistantisolates among Escherichia coli has been an emerging problem. Previous studiesdemonstrated that the mechanisms of resistance to quinolones in E. coli are mainlychromosome-mediated, alterations in target genes and efflux pumps. Plasmid-mediatedquinolone resistance (PMQR) was found to be the primary route of transmission of resistancesubsequently. Currently, studies related to resistance to quinolones among foodborne isolatesof E. coli, however, are limited and primarily focused on clinical isolates. In this study, E. coliisolates from food and clinical patients were determined their susceptibility to14antimicrobial agents, the presence of class I integrons and the mechanisms of resistance toquinolones in E. coli. The objectives were to understand the prevalence and horizontaltransfer of resistance genes in E. coli isolates from different sources and find out the effectivemeasures to control the dissemination of bacterial resistance. The results were as follows:
(1) A total of33E. coli isolated from cooked meat products and66clinical isolates weresubjected to antimicrobial susceptibility testing. Resistance to sulfamethoxazole,trimethoprim/sulfamethoxazole, ampicillin, tetracycline, and streptomycin were observedmost often, whilst amikacin and chloramphenicol exhibited good activity against theseisolates. Eighteen foodborne isolates (54.5%) were multiresistance, expressing resistance tothree or more antimicrobials. Multidrug resistance (MDR) was common in clinical isolates.All isolates were resistance to at least three antimicrobials; nearly50.0%of the isolates wereresistance to at least ten antimicrobials; two isolates were resistance to all14antimicrobialsused in this study.
(2) Class I integrons were detected in18.2%of foodborne isolates and54.5%of clinicalisolates. Integron-positive isolates from food contained three groups of resistance genecassette, consisting of dfrA17-aadA5, dfrA1-aadA1, and dfrA12-orfF-aadA2. Clinical isolatescarried integrons contained seven groups of resistance gene cassette, consisting ofdfrA17-aadA5, dfrA12-orfF-aadA2, dfr2d, aacA4-catB8-aadA1, aadA2+dfrA12-orfF-aadA2,dfrA5, and dfr2d+dfrA17-aadA5.
(3) qnr genes were absent in foodborne isolates. Among clinical isolates, qnr genes were detected in7isolates (2isolates carried qnrA1and5isolates carried qnrS1); aac(6’)-Ib genewas detected in20isolates and eleven carried aac(6’)-Ib-cr gene. Quinolone resistance couldbe transferred to recipient E. coli J53by conjugation from five qnr-positive isolates, with thetransfer frequency in the range of3.4×10~(-5)to2.4×10~(-3). The donors showed higher levels ofresistance to quinolones relative to their transconjugants. DNA sequencing of the PCRproducts covering the entire quinolone-resistance determining regions (QRDRs)demonstrated that mutations in GyrA and/or ParC were present in all donor isolates and therewere no mutations in the target genes among the transconjugants and the recipient. It wassuggested that chromosomal mutations in QRDRs played an important role in mediatinghigh-level quinolones resistance and the presence of qnr alone conferred a low level ofquinolones resistance. Transconjugants showed32-to128-fold and16-to32-fold increasesin the minimal inhibitory concentrations (MICs) of ciprofloxacin and levofloxacinrespectively, and exhibited higher levels of resistance to gentamicin, amikacin, ceftazidime,cefoperazone, cefepime, ampicillin, and sulfamethoxazole relative to recipient.
(4) The levels of qnrS-specific transcripts were compared using real-time quantitativePCR. Three transconjugants obtained in the present study had different ciprofloxacin MICs,however, the results showed no significant differences in the basal expression levels of qnrSgene. The qnrS transcript levels increased when ciprofloxacin and levofloxacin was present,suggesting that the qnrS expression was associated with quinolone resistance.
(5) Five qnr-positive isolates were subjected to plasmid curing by variabletemperature-SDS method and three isolates obtained eliminators successfully with the curingfrequency of60.4%to70.8%. After curing, there were obvious changes in the plasmidpatterns of the three isolates, and qnr genes were not detected in these isolates by PCR. Theresistance profiles of the isolates changed after curing. Before curing, the isolates wereresistant to gentamicin, amikacin, ceftazidime, cefoperazone, cefepime, ampicillin, andsulfamethoxazole; after curing, the isolates become susceptible to these antimicrobials.Nevertheless, no changes were observed in the two isolates which failed to plasmid curing.
（1）对33株分离自熟肉制品的食源性大肠杆菌和66株临床大肠杆菌分离株的药敏试验结果显示，菌株对磺胺甲基异噁唑、复方新诺明、氨苄西林、四环素和链霉素耐药最为严重，对阿米卡星和氯霉素的敏感性最好。食源性菌株中耐受3种或3种以上抗生素的多重耐药菌株有18株（54.5%）；临床分离株中多重耐药情况相对严重，所有菌株均对3种或3种以上抗生素具有耐药性，其中有将近一半的菌株耐10种或10种以上抗生素，有2株大肠杆菌对所用的14种抗生素全部显示出耐药性。
（2）食源性和临床分离的大肠杆菌中I类整合子的阳性率分别为18.2%和54.5%。I类整合子阳性的食源性菌株携带3种不同类型的基因盒，分别为dfrA17-aadA5，dfrA1-aadA1和dfrA12-orfF-aadA2。I类整合子阳性的临床分离株携带7种不同类型的基因盒，分别为dfrA17-aadA5，dfrA12-orfF-aadA2，dfr2d，aacA4-catB8-aadA1，aadA2+dfrA12-orfF-aadA2，dfrA5，dfr2d+dfrA17-aadA5。
（3）食品分离株中未检出qnr基因，而临床分离株中qnr基因阳性共7株，其中2株携带qnrA1，5株携带qnrS1。临床株中aac(6’)-Ib基因阳性菌株共有20株，其中11株经确认为携带其变体基因aac(6’)-Ib-cr。5株qnr阳性菌株通过接合转移成功的将耐药质粒转入受体菌E. coli J53中，接合效率分别在3.4×10~(-5)到2.4×10~(-3)之间。供体菌对喹诺酮类耐药水平明显高于其接合子。通过对供体菌、接合子和受体菌的QRDRs检测发现，5株供体菌均在GyrA亚基和/或ParC亚基存在氨基酸突变，其相应的接合子及受体菌J53的QRDRs均未发现突变。这说明染色体突变介导了较高水平的喹诺酮耐药；qnr基因的单独存在可使菌株对喹诺酮类药物的敏感性降低，从而介导了低水平的耐药。相对于受体菌来说，接合子对环丙沙星和左氧氟沙星的MIC值分别增加了32～128倍和16～32倍，对庆大霉素、阿米卡星、头孢他啶、头孢哌酮、头孢吡肟、氨苄西林和磺胺甲基异噁唑的耐药性也有大幅提高。
（4）通过实时荧光定量PCR发现，筛选出的三株qnrS阳性接合子对环丙沙星的MIC值有所不同，但是qnrS基因的表达水平却基本相同。在环丙沙星和左氧氟沙星的作用下，qnrS的表达水平显著升高。结果表明qnrS基因的表达水平与喹诺酮类耐药程度有关。
（5）5株qnr阳性菌株经SDS-高温高浓度双重处理交替培养法处理后，有3株成功的筛选出了消除子，消除率在60.4%到70.8%之间。这3株菌在质粒消除后质粒图谱发生了明显变化，并且经PCR扩增反应未检出qnr基因。质粒消除后，这3株菌的耐药谱也发生了变化，对庆大霉素、阿米卡星、头孢他啶、头孢哌酮、头孢吡肟、氨苄西林和磺胺甲基异噁唑的耐药性发生了逆转，由原本的耐药变为敏感。而未成功消除耐药质粒菌株的耐药谱则没有发生变化。
As quinolones used widely in clinical medicine, the increasing prevalence of resistantisolates among Escherichia coli has been an emerging problem. Previous studiesdemonstrated that the mechanisms of resistance to quinolones in E. coli are mainlychromosome-mediated, alterations in target genes and efflux pumps. Plasmid-mediatedquinolone resistance (PMQR) was found to be the primary route of transmission of resistancesubsequently. Currently, studies related to resistance to quinolones among foodborne isolatesof E. coli, however, are limited and primarily focused on clinical isolates. In this study, E. coliisolates from food and clinical patients were determined their susceptibility to14antimicrobial agents, the presence of class I integrons and the mechanisms of resistance toquinolones in E. coli. The objectives were to understand the prevalence and horizontaltransfer of resistance genes in E. coli isolates from different sources and find out the effectivemeasures to control the dissemination of bacterial resistance. The results were as follows:
(1) A total of33E. coli isolated from cooked meat products and66clinical isolates weresubjected to antimicrobial susceptibility testing. Resistance to sulfamethoxazole,trimethoprim/sulfamethoxazole, ampicillin, tetracycline, and streptomycin were observedmost often, whilst amikacin and chloramphenicol exhibited good activity against theseisolates. Eighteen foodborne isolates (54.5%) were multiresistance, expressing resistance tothree or more antimicrobials. Multidrug resistance (MDR) was common in clinical isolates.All isolates were resistance to at least three antimicrobials; nearly50.0%of the isolates wereresistance to at least ten antimicrobials; two isolates were resistance to all14antimicrobialsused in this study.
(2) Class I integrons were detected in18.2%of foodborne isolates and54.5%of clinicalisolates. Integron-positive isolates from food contained three groups of resistance genecassette, consisting of dfrA17-aadA5, dfrA1-aadA1, and dfrA12-orfF-aadA2. Clinical isolatescarried integrons contained seven groups of resistance gene cassette, consisting ofdfrA17-aadA5, dfrA12-orfF-aadA2, dfr2d, aacA4-catB8-aadA1, aadA2+dfrA12-orfF-aadA2,dfrA5, and dfr2d+dfrA17-aadA5.
(3) qnr genes were absent in foodborne isolates. Among clinical isolates, qnr genes were detected in7isolates (2isolates carried qnrA1and5isolates carried qnrS1); aac(6’)-Ib genewas detected in20isolates and eleven carried aac(6’)-Ib-cr gene. Quinolone resistance couldbe transferred to recipient E. coli J53by conjugation from five qnr-positive isolates, with thetransfer frequency in the range of3.4×10~(-5)to2.4×10~(-3). The donors showed higher levels ofresistance to quinolones relative to their transconjugants. DNA sequencing of the PCRproducts covering the entire quinolone-resistance determining regions (QRDRs)demonstrated that mutations in GyrA and/or ParC were present in all donor isolates and therewere no mutations in the target genes among the transconjugants and the recipient. It wassuggested that chromosomal mutations in QRDRs played an important role in mediatinghigh-level quinolones resistance and the presence of qnr alone conferred a low level ofquinolones resistance. Transconjugants showed32-to128-fold and16-to32-fold increasesin the minimal inhibitory concentrations (MICs) of ciprofloxacin and levofloxacinrespectively, and exhibited higher levels of resistance to gentamicin, amikacin, ceftazidime,cefoperazone, cefepime, ampicillin, and sulfamethoxazole relative to recipient.
(4) The levels of qnrS-specific transcripts were compared using real-time quantitativePCR. Three transconjugants obtained in the present study had different ciprofloxacin MICs,however, the results showed no significant differences in the basal expression levels of qnrSgene. The qnrS transcript levels increased when ciprofloxacin and levofloxacin was present,suggesting that the qnrS expression was associated with quinolone resistance.
(5) Five qnr-positive isolates were subjected to plasmid curing by variabletemperature-SDS method and three isolates obtained eliminators successfully with the curingfrequency of60.4%to70.8%. After curing, there were obvious changes in the plasmidpatterns of the three isolates, and qnr genes were not detected in these isolates by PCR. Theresistance profiles of the isolates changed after curing. Before curing, the isolates wereresistant to gentamicin, amikacin, ceftazidime, cefoperazone, cefepime, ampicillin, andsulfamethoxazole; after curing, the isolates become susceptible to these antimicrobials.Nevertheless, no changes were observed in the two isolates which failed to plasmid curing.
引文
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