季銨鹽類(lèi)消毒劑及大腸桿菌對(duì)其耐藥性研究進(jìn)展

鄒立扣，吳國(guó)艷,2，程 琳，何雪梅,2，郭麗娟,2，龍 梅,2

季銨鹽類(lèi)消毒劑及大腸桿菌對(duì)其耐藥性研究進(jìn)展

鄒立扣1，吳國(guó)艷1,2，程 琳1，何雪梅1,2，郭麗娟1,2，龍 梅1,2

（1.四川農(nóng)業(yè)大學(xué) 都江堰校區(qū)微生物學(xué)實(shí)驗(yàn)室，四川 都江堰 611830；2.四川農(nóng)業(yè)大學(xué)資源環(huán)境學(xué)院，四川 成都 611130）

研究表明，食源性細(xì)菌消毒劑耐藥嚴(yán)重，大腸桿菌是食品污染狀況及耐藥性監(jiān)測(cè)的指示菌，對(duì)季銨鹽類(lèi)消毒劑表現(xiàn)出比革蘭氏陽(yáng)性菌更強(qiáng)的抗性，且大腸桿菌對(duì)消毒劑與抗生素耐藥性可共傳播。鑒于此，本文綜述了季銨鹽類(lèi)消毒劑的結(jié)構(gòu)與種類(lèi)、作用機(jī)制、大腸桿菌消毒劑耐藥產(chǎn)生、耐藥基因、基因型與表型的關(guān)系以及 與抗生素耐藥共傳播機(jī)制等的研究進(jìn)展。食源性大腸桿菌對(duì)季銨鹽類(lèi)消毒劑抗性的耐藥機(jī)制研究很少，研究大腸桿菌對(duì)季銨鹽類(lèi)消毒劑耐藥性，可為消毒劑的規(guī)范使用以及食源性大腸桿菌的防控提供科學(xué)依據(jù)及理論基礎(chǔ)。

大腸桿菌；季銨鹽類(lèi)；消毒劑；耐藥

隨著社會(huì)經(jīng)濟(jì)的發(fā)展與人民生活水平的提高，食品安全問(wèn)題已經(jīng)成為人們關(guān)注的焦點(diǎn)，而食品污染中致病微生物引起的食 源性疾病是影響食品安全的最主要因素之一[1-2]。大腸桿菌（Escherichia coli）被很多國(guó)家作為各類(lèi)食品污染狀況的指示菌進(jìn)行檢測(cè)，是保障食品安全的重要指標(biāo)之一，其可導(dǎo)致腹瀉，感染某些致病性較強(qiáng)的血清型時(shí)還可能致命，如O157∶H7引起的出血性腹瀉和溶血性尿毒綜合征（heomlytic uremic syndrome，HUS）等[3]。季銨鹽類(lèi)化合物（quaternary ammonium compounds，QACs）消毒劑常被用來(lái)防止食品工業(yè)中致病微生物的擴(kuò)散及污染[4]，可以有效減少食品中的病原微 生物，然而，抗菌藥物的廣泛或不合理使用可產(chǎn)生篩選壓力，QACs消毒劑的使用會(huì)導(dǎo)致細(xì)菌的適應(yīng)和耐藥菌的生長(zhǎng)，是消毒劑抗性增加的潛在動(dòng)力[5]。目前，對(duì)革蘭氏陽(yáng)性細(xì)菌消毒劑耐藥及耐藥基因流行已有較多報(bào)道和研究，如葡萄球菌（Staphylococcus spp.）及腸球菌（Enterococcus spp.）等[6-8]。相對(duì)革蘭氏陽(yáng)性細(xì)菌，革蘭氏陰性細(xì)菌對(duì)消毒劑表現(xiàn)出更強(qiáng)的抗性[9]，但對(duì)革蘭氏陰性細(xì)菌，特別是食源性革蘭氏陰性細(xì)菌對(duì)QACs抗性的發(fā)生及耐藥機(jī)制研究很少，全面調(diào)查大腸桿菌對(duì)QACs消毒劑耐藥性已經(jīng)迫在眉睫[10-11]。鑒于此，本文綜述了季銨鹽類(lèi)消毒劑的結(jié)構(gòu)與種類(lèi)、作用機(jī)制、大腸桿菌消毒劑耐藥產(chǎn)生、耐藥基因、基因型與表型的關(guān)系以及與抗生素耐藥共傳播機(jī)制等研究進(jìn)展。

1 食源性大腸桿菌簡(jiǎn)介

大腸桿菌是人和動(dòng)物重要的共生腸道微生物，絕大部分大腸桿菌屬于腸道正常菌群，但仍有部分菌株可導(dǎo)致人和動(dòng)物感染、發(fā)病，這些致病性大腸桿菌可引起人類(lèi)的腸胃炎、尿道感染、新生兒敗血癥或腦膜炎等。根據(jù)所含毒力因子的種類(lèi)，致病性大腸桿菌可分為5 類(lèi)，腸致病性大腸桿菌（enteropathogenic E. coli，EPEC）、腸產(chǎn)毒性大腸桿菌（enterotoxigenic E. coli，ETEC）、腸侵襲性大腸桿菌（enteroinvasive E. coli，EIEC）、腸黏附性大腸桿菌（enteroaggregative E. coli，EAEC）及腸出血性大腸桿菌（enterohemorrhagic E. coli，EHEC）等，這些大腸桿菌均可通過(guò)食物鏈進(jìn)入人體并對(duì)人類(lèi)的健康構(gòu)成威脅[3]。食品中污染大腸桿菌主要發(fā)生在食品生產(chǎn)、處理、分配及零售等過(guò)程，20世紀(jì)以來(lái)，由于奶制品、水果、蔬菜、甜點(diǎn)、肉類(lèi)及水產(chǎn)品等食品污染，引發(fā)了大腸桿菌的全球暴發(fā)，而暴發(fā)的場(chǎng)所有飯店、快餐店、自助餐廳、野餐、養(yǎng)老院及社區(qū)等[12]。除了具有較強(qiáng)的致病力，大腸桿菌可通過(guò)自身基因突變或捕獲外源耐藥基因產(chǎn)生耐藥性，也可將耐藥基因通過(guò)質(zhì)粒及整合子等傳遞到在腸道或環(huán)境中與其共存的其他細(xì)菌，因此，被認(rèn)為是耐藥性監(jiān)測(cè)中良好的指示菌，目前發(fā)現(xiàn)，眾多食品特別是肉類(lèi)食品中分離出的大腸桿菌抗生素耐藥嚴(yán)重[13-14]，是抗生素耐藥大腸桿菌重要的“貯存庫(kù)”[15-16]，這些耐藥菌可通過(guò)被污染的食品使人感染，對(duì)人類(lèi)的健康構(gòu)成威脅[17]。

2 季銨鹽類(lèi)消毒劑結(jié)構(gòu)與種類(lèi)

消毒劑是食品生產(chǎn)清洗、消毒過(guò)程中使用的主要化合物，可保證食品產(chǎn)品的微生物安全。為了避免在食品和普通消費(fèi)者市場(chǎng)中微生物污染及感染的風(fēng)險(xiǎn)，消毒劑在共同衛(wèi)生中使用正呈現(xiàn)增長(zhǎng)的趨勢(shì)，消毒劑中有眾多的化學(xué)活性物質(zhì)，主要用于消毒與保存。常用的消毒防腐劑有季胺鹽類(lèi)化合物、酚類(lèi)化合物、雙胍類(lèi)、碘及其復(fù)合物、醛類(lèi)、過(guò)氧化物和銀化合物等，這些消毒劑有些已經(jīng)使用了近百年，相對(duì)于抗生素，消毒劑可表現(xiàn)出更寬的廣譜活性，且具有多個(gè)靶位點(diǎn)，而抗生素可能只有一個(gè)特異的胞內(nèi)位點(diǎn)[18]。

在食品工業(yè)中，常規(guī)清潔和控制食品、環(huán)境中可產(chǎn)生嚴(yán)重疾病的病原微生物水平十分重要，清潔步驟中消毒劑的使用，可以減少表面微生物的生存[19-20]。QACs消毒劑由于具有無(wú)腐蝕、無(wú)刺激性、較穩(wěn)定且毒性低等優(yōu)點(diǎn)而被廣泛地用于食品和環(huán)境的消毒[21-22]。QACs消毒劑亦被作為獸藥控制動(dòng)物疾病[23]，使用QACs消毒劑可降低禽類(lèi)養(yǎng)殖中細(xì)菌污染[24-25]。QACs包含一個(gè)4價(jià)氮， 基本化學(xué)結(jié)構(gòu)為N+R1R2R3R4X-，其中R代表一個(gè)氫原子、一個(gè)烷基或烷基被替代的其他功能基團(tuán)，X代表一個(gè)陰離子，比如氯或溴等[26]（圖1）。

圖1 季銨鹽類(lèi)消毒劑結(jié)構(gòu)通式[18]Fig.1 General chemical structur e of QACs[18]

美國(guó)國(guó)家環(huán)境保護(hù)局（U.S. Environmental Protection Agency，USEPA）把QACs分為四大類(lèi)[27]，而根據(jù)功能基團(tuán)的不同，可分為三大類(lèi)，具體見(jiàn)表1。

表1 QACs消毒劑的分類(lèi)Table 1 Classification of QAC disinfectants

目前，用于衛(wèi)生消毒的QACs種類(lèi)主要有N-烷基二甲基芐基氯化銨（N-alkyl dimethyl benzyl ammonium chloride，A D BAC）、苯扎氯銨（benzalkonium chloride，BC）、溴化十六烷基三甲銨（cetyltrimethylammonium bromide，CTAB）、溴化溴棕三甲銨（cetrimide bromi de，CB）、氯化十六烷基吡啶（cetylpyridinium chloride，CTPC）、雙十烷基二甲基氯化銨（N,N-didecyl-N,N-dimethylammonium chloride，DDAC）、司拉氯銨（stearalkonium chloride）及芐索氯銨（benzethonium chloride）等，其中BC、CTAB及ADBAC等已被廣泛應(yīng)用于食品工業(yè)，其中BC、CB等已使用超過(guò)40年[26]，幾種主要的QACs結(jié)構(gòu)見(jiàn)圖2。

a. ADBAC[28]/BC[29]；b. CB[28]；c. CTPC[28]；d. CTAB[30]；e. DDAC[27]。

圖3 QACs反應(yīng)機(jī)理示意圖[26]Fig.3 C artoon showing the mechanism of action of QACs[26]

3 季銨鹽類(lèi)消毒劑作用機(jī)制及殘留檢測(cè)

3.1 作用機(jī)制

細(xì)菌細(xì)胞表面攜帶負(fù)電荷，常通過(guò)陽(yáng)性離子維持細(xì)胞膜的穩(wěn)定性。QACs是陽(yáng)離子型表面活性劑和抗菌劑，可通過(guò)正電荷與細(xì)胞膜相互作用，其抗菌活性是N-烷基的功能。N-烷基賦予QACs親脂性特征，通過(guò)陽(yáng)性氮基團(tuán)與細(xì)菌細(xì)胞膜上酸性磷脂的結(jié)合，疏水端整合入細(xì)菌疏水膜的核心，在高濃度時(shí)，QACs通過(guò)形成混合膠束聚集來(lái)溶解疏水細(xì)胞膜成分[26]（圖3）?？傮w來(lái)說(shuō)，QACs發(fā)揮抗菌活性主要依靠破壞和變性蛋白和酶、破壞細(xì)胞膜整體性和使細(xì)胞內(nèi)含物泄漏等[26,31]。對(duì)不同微生物的抗菌活性取決于烷基鏈的長(zhǎng)度：鏈長(zhǎng)12～14烷基的QACs對(duì)革蘭氏陽(yáng)性細(xì)菌和酵母表現(xiàn)最適活性；14～16烷基的QACs對(duì)革蘭氏陰性細(xì)菌表現(xiàn)最適活性；鏈長(zhǎng)小于4或大于18的QACs幾乎無(wú)活性[26]。除對(duì)細(xì)菌具有抗菌活性，QACs消毒劑對(duì)一些病毒、真菌、酵母和原生動(dòng)物也具有活性[32]。

3.2 殘留檢測(cè)

研究表明QACs殘留可危害動(dòng)物健康[33]，食品中殘留的季銨鹽類(lèi)消毒劑對(duì)人鼻上皮細(xì)胞有害，可引發(fā)、加重鼻炎[34]。同時(shí)，殘留消毒劑可導(dǎo)致細(xì)菌耐藥性，歐盟規(guī)定水果和蔬菜中QACs殘留不得超過(guò)0.01 mg/kg，因此對(duì)季銨鹽類(lèi)消毒劑殘留檢測(cè)凸顯重要。在眾多方法中，高效液相色譜（high performance liquid chromatography，HPLC）、液相質(zhì)譜（liquid chromatograph-mass spectrometer，LC-MS）方法被成功用于檢測(cè)QACs[35]。Shen等[29]利用HPLC系統(tǒng)反相模式檢測(cè)了阿奇霉素眼藥水中的BC，選用Venusil- XBP（L）-C18（150 mm×4.6 mm，5 μm）柱，柱溫50 ℃，流動(dòng)相甲醇-磷酸鉀 （16∶5，V/V），樣品前處理中使用去蛋白步驟，結(jié)果表明HPLC是監(jiān)測(cè)阿奇霉素眼藥水中的BC含量的有效方法。 Ford等[36]建立了在HPLC結(jié)合電噴霧電離質(zhì)譜方法基礎(chǔ)上的對(duì)QACs定性及定量檢測(cè)方法，對(duì)BC的檢測(cè)限達(dá)到了3 ng/mL，且可同時(shí)檢測(cè)苯基、雙烷基二甲基氨鹽化合物，此方法已成功應(yīng)用于分析衛(wèi)生采樣裝置、產(chǎn)品及游泳池水。MALDI-TOFMS方法亦被用于分析商業(yè)產(chǎn)品漱口水中QACs的組成，研究發(fā)現(xiàn)除了產(chǎn)品中標(biāo)明的CPC、四烷基氨基氨鹽化合物及三烷基氨鹽化合物外，還包含一個(gè)復(fù)雜的氨鹽類(lèi)混合物[28]。以ABDAC、四烷基氨基氨鹽化合物為檢測(cè)對(duì)象，研究表明毛細(xì)血管電泳（capillary electrophoresis，CE）法要比電噴霧質(zhì)譜分離效率高，檢測(cè)限要高于兩個(gè)數(shù)量級(jí)[37]。

4 大腸桿菌對(duì)季銨鹽類(lèi)消毒劑耐藥性

4.1 大腸桿菌對(duì)消毒劑耐藥性產(chǎn)生基礎(chǔ)

QACs的使用是消毒劑抗性增加的潛在的重要?jiǎng)恿?，食品工業(yè)中QACs的廣泛使用會(huì)導(dǎo)致細(xì)菌的適應(yīng)和耐藥菌的生長(zhǎng)[5]。QACs可以有效減少食品中病原微生物，為了能快速殺死病原菌，在屠宰、肉類(lèi)處理，特別是那些小且難接觸到的區(qū)域，消毒劑的使用濃度要遠(yuǎn)高于它們對(duì)微生物的最小抑菌濃度[38-39]，這種濃度可以達(dá)到千倍的最小抑菌濃度（minimal inhibitory concentration，MIC）值，而細(xì)菌要戰(zhàn)勝快速、猛烈的消毒劑攻擊并產(chǎn)生耐藥生幾乎是不可能的。大部分QACs在應(yīng)用后不需要用水沖洗或沖洗不及時(shí)等，因此細(xì)菌與QACs的接觸時(shí)間可以延長(zhǎng)，長(zhǎng)時(shí)間暴露于低濃度的QACs，可以使微生物處于亞抑制濃度中，如此，會(huì)使那些只對(duì)QACs高濃度MIC敏感的細(xì)菌才會(huì)生存下來(lái)[40]，細(xì)菌對(duì)消毒劑的耐藥性逐漸增大，最終導(dǎo)致消毒劑在食品行業(yè)中使用失敗，并出現(xiàn)影響人類(lèi)健康等嚴(yán)重的問(wèn)題。

如今，對(duì)消毒劑耐藥性研究的對(duì)象主要為革蘭氏陽(yáng)性菌中的葡萄球菌（Staphylococcus spp.），由于消毒劑的過(guò)量使用，導(dǎo)致葡萄球菌，特別是耐甲氧西林金黃色葡萄球菌（methicillin-resistant Staphylococcus aureus，MRSA）對(duì)消毒劑的耐藥。相對(duì)革蘭氏陽(yáng)性細(xì)菌，革蘭氏陰性細(xì)菌對(duì)消毒劑表現(xiàn)出更強(qiáng)的抗性[9]。大腸桿菌對(duì)QACs消毒劑的MICs遠(yuǎn)高于葡萄球菌，如大腸桿菌對(duì)BC的MIC為50 mg/L，遠(yuǎn)高于葡萄球菌的0.5 mg/L[18]，假單胞菌（Pseudomonas sp.）對(duì)BC的MIC達(dá)到了200 mg/L，遠(yuǎn)高于葡萄球菌的4～11 mg/L[41]，革蘭氏陰性細(xì)菌對(duì)QACs的高抗性源自于所攜帶的特異性耐藥基因[42]。

4.2 大腸桿菌對(duì)季銨鹽類(lèi)耐藥基因型

迄今為止，有7 種不同質(zhì)粒介導(dǎo)的QAC特異的抗性基因在革蘭氏陰性細(xì)菌大腸桿菌中被發(fā)現(xiàn)，包括qacE、qacEΔ1、qacF、qacG、qacH、qacI及sugE[43-45]。這些基因編碼外排泵蛋白賦予對(duì)QACs的抗性，屬于小多重抗性（small multiple resistance，SMR）蛋白家族[42,45]，SMR家族基因可由質(zhì)?；蛘献咏閷?dǎo)，對(duì)QACs高濃度MICs的菌株經(jīng)常通過(guò)獲得可移動(dòng)基因元件，如質(zhì)粒、1型整合子等獲得這些消毒劑基因[46]，而1型整合子大多存在于可接合的質(zhì)粒上[47-48]，因此，qac、sugE（p）基因可在革蘭氏陰性細(xì)菌中水平及垂直傳播[49-50]。由于質(zhì)粒型消毒劑基因的可傳播性，以及具有與抗生素耐藥基因的共傳播特性，相對(duì)于染色體編碼QACs特異性耐藥基因，qac、sugE（p）基因在消毒劑耐藥中扮演著重要的角色。qacE、qacEΔ1基因發(fā)現(xiàn)存在于革蘭氏陰性菌質(zhì)粒上1型整合子3端[51-52]，qacEΔ1基因是qacE基因的突變?nèi)毕蒹w[43]。QacEΔ1蛋白對(duì)季銨鹽類(lèi)消毒劑和染料的耐藥水平低于QacE，這些差異是由于QacEΔ1蛋白失去了第四個(gè)跨膜片段和羧基末端的高度保守殘基所造成的[53]。qacG基因報(bào)道由1型整合子介導(dǎo)[45]，qacF、qacH、qacI基因與qacE的同源率達(dá)到67.8%，亦常發(fā)現(xiàn)于革蘭氏陰性細(xì)菌質(zhì)粒介導(dǎo)的整合子[54-55]、質(zhì)粒pB8及IncP-1βpR751上[56]。與qac基因類(lèi)似，sugE基因被發(fā)現(xiàn)存在于質(zhì)粒，首先發(fā)現(xiàn)于肺炎克雷伯氏菌（Klebsiella pneumoniae）β-內(nèi)酰胺藥物抗性質(zhì)粒pTKH11上[57]，之后，從大腸桿菌、沙門(mén)氏菌分離的質(zhì)粒上也檢測(cè)出sugE（p）基因[39,58-60]。對(duì)于sugE基因，Chung等[61]認(rèn)為大腸桿菌（E. coli）中的sugE的超量表達(dá)，表現(xiàn)出對(duì)部分QACs耐藥；Son等[62]認(rèn)為sugE僅僅可通過(guò)一個(gè)氨基酸突變即可表現(xiàn)出對(duì)QAC抗性。最新研究表明，qac、sugE（p）基因共存于多重耐藥（multi drug resistance，MDR）質(zhì)粒：InA/C、pSN254上[60]，可介導(dǎo)高水平消毒劑耐藥。

除以上基因之外，某些非特異性外排基因，如大腸桿菌[63]以及大腸桿菌O157∶H7[64]中質(zhì)粒介導(dǎo)TehA基因[65]，耐藥節(jié)結(jié)化細(xì)胞分化（resistance nodulation cell division，RND）家族外排泵AcrAB-TolC也表現(xiàn)出對(duì)QACs的非特異性的耐藥，但其表達(dá)與調(diào)控基因marOR、soxS的表達(dá)密切相關(guān)[10]。另有5 種染色體編碼基因sugE（c）（染色體型sugE）、emrE、ydgE/ydgF及mdfA等也特異抗性地賦予對(duì)QACs的抗性，但不具傳播性[66-67]。綜上，質(zhì)粒介導(dǎo)的QACs消毒劑耐藥基因不僅在革蘭陽(yáng)性菌中已經(jīng)流行，在革蘭氏陰性菌中也已經(jīng)存在，質(zhì)粒介導(dǎo)消毒劑基因傳播危害性較大，應(yīng)引起重視。

4.3 大腸桿菌對(duì)季銨鹽類(lèi)耐藥基因型與表型關(guān)系

不同的消毒劑基因介導(dǎo)對(duì)QACs的不同程度的耐藥，目前，已知部分消毒劑基因與其表型之間的關(guān)系[18,66]，但尚有基因與表型之間的關(guān)系未建立。鑒于相關(guān)流行病學(xué)調(diào)查不夠系統(tǒng)、全面，關(guān)于qac基因型與表型之間的關(guān)系，有兩種觀點(diǎn)。一種觀點(diǎn)主要基于對(duì)qacEΔ1基因的研究，此觀點(diǎn)認(rèn)為，qac基因介導(dǎo)低水平QACs抗性，不同qac基因攜帶株對(duì)QACs的MICs無(wú)明顯差異[43]。在綠膿假單胞菌（Pseudomonas aeruginosa）中，qacEΔ1基因并沒(méi)有對(duì)QACs成員之一的苯扎氯銨表現(xiàn)高抗性[68]。其中的一個(gè)解釋是基于qac基因介導(dǎo)對(duì)眾多陽(yáng)離子化合物表現(xiàn)抗性，從而可能導(dǎo)致對(duì)QACs底物表現(xiàn)非高水平的特異性[66,69]。qac基因介導(dǎo)對(duì)QACs的抗性，同時(shí)可對(duì)30多種親脂性陽(yáng)離子化合物表現(xiàn)抗性，這些化合物至少隸屬于12個(gè)不同的化學(xué)家族，包括單價(jià)陽(yáng)離子化合物，如吖啶黃、結(jié)晶紫及絕大部分QACs等，雙價(jià)陽(yáng)離子化合物包括雙胍類(lèi)、聯(lián)脒及部分QACs等[70]。qacEΔ1、qacE啟動(dòng)子的類(lèi)型與表達(dá)水平也可能導(dǎo)致對(duì)QACs的低水平耐藥[42]。然而另一觀點(diǎn)認(rèn)為，qac基因和對(duì)不同陽(yáng)離子化合物抗性之間存在緊密的聯(lián)系，由于qac基因的表達(dá)，細(xì)菌對(duì)消毒劑的抗性逐漸增加[71]。Smith等[72]研究發(fā)現(xiàn)qac基因陰性與陽(yáng)性菌株間QACs的MICs有顯著差異，攜帶qac基因菌株MIC值可為不攜帶該基因菌株的2 倍。質(zhì)粒介導(dǎo)的qacG基因可使菌株對(duì)消毒劑的MIC值高于敏感菌株5 倍，且暴露在20 mg/L QAC中的存活時(shí)間高于敏感株1萬(wàn) 倍[73]。pNVH01質(zhì)粒上攜帶的qacJ基因陽(yáng)性菌株對(duì)BC和CATB消毒劑的MIC值分別高于陰性菌株的4.5～5.5 倍[46]。

除此之外，目前尚缺乏對(duì)革蘭氏陰性細(xì)菌中qacF、qacH、qacI及sugE（p）等基因與消毒劑耐藥表型關(guān)系的研究，因此，需系統(tǒng)調(diào)查質(zhì)粒介導(dǎo)消毒基因的耐藥表型，在此基礎(chǔ)上，確立消毒劑基因與對(duì)QACs的MICs之間的對(duì)應(yīng)關(guān)系。

4.4 季銨鹽類(lèi)消毒劑與抗生素耐藥基因共傳播

QACs被廣泛使用，然而QACs對(duì)抗生素抗性的潛在的篩選壓力卻很少引起關(guān)注。Soumet等[74]評(píng)估了大腸桿菌菌株反復(fù)暴露于不同QACs后，對(duì)QACs和抗生素敏感性變化的影響，研究發(fā)現(xiàn)，菌株同時(shí)表現(xiàn)對(duì)QACs、抗生素的耐藥，QACs在亞抑制濃度下的過(guò)度使用可導(dǎo)致對(duì)抗生素耐藥菌株的篩選，并帶來(lái)公共安全風(fēng)險(xiǎn)。QACs類(lèi)消毒劑的暴露使用，發(fā)揮著篩選壓力的 作用，并可以產(chǎn)生共耐藥的基因，編碼對(duì)消毒劑和抗生素的共同抗性[75]。從臨床樣品分離的高水平QAC的MICs值的大腸桿菌菌株同時(shí)與抗生素抗性密切相關(guān)[76]，BC耐藥菌株對(duì)大環(huán)內(nèi)酯類(lèi)、苯唑西林的耐藥率明顯高于非耐藥菌[6]。細(xì)菌對(duì)消毒劑和抗生素抗性之間存在關(guān)聯(lián)，消毒劑和抗生素可以共篩選（co-selection）同時(shí)具有對(duì)消毒劑和抗生素抗性的細(xì)菌。為了生存，共篩選的微生物必須獲得對(duì)2 種以上不同抗菌物質(zhì)的抗性。共篩選可以通過(guò)兩種機(jī)制藥發(fā)生，一種機(jī)制為交叉耐藥（cross-resistance），指不同的藥物對(duì)同一靶位作用或使用同一作用途徑；一般由單個(gè)外排泵介導(dǎo)，同時(shí)可以泵出QACs和其他抗菌物質(zhì)[77-78]。如葡萄球菌中qacC基因可賦予宿主對(duì)β-內(nèi)酰胺藥物的抗性[79]。另一種機(jī)制為共同耐藥（coresistance），指賦予抗性表型的基因存在于同一個(gè)移動(dòng)基因元件上，比如質(zhì)?；蛘献印＿@些基因元件包括兩個(gè)或更多的抗性基因或基因單位[80-81]。QACs和抗生素的共耐藥被認(rèn)為與醫(yī)療保健、食品設(shè)備中使用QAC有關(guān)[50]。不管是交叉耐藥還是共同耐藥，最終結(jié)果是一致的：即對(duì)一種藥物抗性的發(fā)展同時(shí)伴隨對(duì)另一種藥物抗性的出現(xiàn)。在革蘭氏陰性細(xì)菌中，qac基因經(jīng)常存在于質(zhì)粒介導(dǎo)的1型整合子上，這些整合子同時(shí)攜帶不同的抗生素抗性基因，因此，qac基因和抗生素耐藥基因可同時(shí)表達(dá)，從而表現(xiàn)出共同耐藥[82]。qacEΔ1基因常發(fā)現(xiàn)于1型整合子上，同時(shí)包括sul I磺胺類(lèi)藥物抗性基因[43,83]，qacEΔ1亦被發(fā)現(xiàn)與新型金屬β-內(nèi)酰胺酶基因blaNDM-1同時(shí)存在于1型整合子上[84]。qacG基因與其他抗性基因blaIMP-4、aacA4、qnrB4等一起共存在沙門(mén)氏菌質(zhì)粒I型整合子上[49]。sugE（p）基因發(fā)現(xiàn)與抗生素抗性基因blaCMY-2、sulI、aadA及tet RA等共存于大腸桿菌或沙門(mén)氏菌多重耐藥質(zhì)粒IncA/C、pSN254上[39,58-60]。在可移動(dòng)的基因元件上攜帶QAC耐藥基因可保證抗性通過(guò)水平基因轉(zhuǎn)移傳播于菌群中[50]。消毒劑抗性和抗生素抗性可以“共定植”，因此對(duì)其中一個(gè)篩選可導(dǎo)致另一個(gè)抗性的篩選[85]。

5 結(jié) 語(yǔ)

目前，國(guó)內(nèi)外對(duì)食源性大腸桿菌耐藥基因流行特征及耐藥機(jī)制等研究尚不深入，調(diào)查食源性大腸桿菌消毒劑耐藥基因流行特征及傳播機(jī)制已經(jīng)迫在眉睫，開(kāi)展大腸桿菌對(duì)消毒劑耐藥流行病學(xué)及機(jī)制研究，對(duì)防控消毒劑耐與抗生素藥性與基因傳播有著重要作用，為QACs的規(guī)范使用提供依據(jù)和理論基礎(chǔ)，并為食品工業(yè)中食源性大腸桿菌及革蘭氏陰性菌的防控提供科學(xué)依據(jù)。

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Progress in Research on the Resistance of Escherichia coli to Quaternary Ammonium Compounds (QACs)

ZOU Li-kou1, WU Guo-yan1,2, CHENG Lin1, HE Xue-mei1,2, GUO Li-juan1,2, LONG Mei1,2
(1. Laboratory of Microbiology, Dujiangyan Campus of Sichuan Agricultural University, Dujiangyan 611830, China; 2. College of Resources and Environment, Sichuan Agricultural University, Chengdu 611130, China)

Current studies have demonstrated the serious disinfectant resistance in food-borne bacteria. Escherichia coli as an indicator bacterium for food contamination and drug resistance reveals much higher resistance to quaternary ammonium compounds (QACs) than do Gram-positive bacteria. In addition, the resistance to QACs and antibiotics can be disseminated and co-transmitted, thus resulting in co-selected disinfectant and antibiotics-resistant bacteria. Therefore, the chemical structure, species and mechanism of action of QACs, the genetic mechanism as well as genotype and phenotype underlying QACs resistance of Escherichia coli, and the mechanism of co-transmission with antibiotic resistance are summarized in this article. To date, little is known about the mechanism of disinfectant resistance in food-borne E. coli. Thus, further research on the disinfectant resistance is needed. Understanding the mechanism of QACs resistance of E. coli can provide a theoretical and scientific basis for regulating the use of disinfectants and preventing food-borne E. coli infections.

Escherichia coli; quaternary ammonium compounds; disinfectant; antibiotic resistance

Q93；TS207.4

A

1002-6630（2014）17-0338-08

10.7506/spkx1002-6630-201417063

2013-08-07

四川省教育廳重點(diǎn)基金項(xiàng)目（10ZA055）；四川省教育廳青年基金項(xiàng)目（13ZB0282）；教育部“長(zhǎng)江學(xué)者和創(chuàng)新團(tuán)隊(duì)發(fā)展計(jì)劃”項(xiàng)目（IRT13083）

鄒立扣（1979—），男，教授，博士，研究方向?yàn)槲⑸锓肿由飳W(xué)、食品安全。E-mail：zoulkcn@hotmail.com