Role of the two component signal transduction system CpxAR in conferring cefepime and chloramphenicol resistance in Klebsiella pneumoniae NTUH-K2044.
Role of the two component signal transduction system CpxAR in conferring cefepime and chloramphenicol resistance in Klebsiella pneumoniae NTUH-K2044.
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两个组件信号转导系统CPXAR在肺炎肺炎NTUH-K2044中赋予头孢酸和氯霉素耐药性中的作用。
DOI：
10.1371/journal.pone.0033777
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Rajamohan G
中科院分区：
文献类型：
--
作者：
Srinivasan VB;Vaidyanathan V;Mondal A;Rajamohan G
肺炎克雷伯氏菌是革兰氏阴性、非运动性、兼性厌氧菌，属于变形菌门中γ-变形菌纲的肠杆菌科。多药耐药克雷伯氏菌由于产生超广谱β-内酰胺酶的菌株的出现，肺炎已经在世界范围内引起了主要的治疗问题。双组分系统作为一种基本的刺激-反应耦合机制，使生物体能够感知和响应许多不同环境条件（包括抗生素胁迫）的变化。在本研究中，我们通过产生来自高粘液K1菌株K的CpxA/CpxR组分缺陷的同基因突变体（ΔcpxAR）来研究未表征的cpxAR操纵子在细菌生理学和抗菌素耐药性中的作用。pneumoniae NTUH-K2044.ΔcpxAR的行为是在不利条件下确定的，在胃肠道环境中遇到的再现应力和删除导致对胆汁、渗透压和酸应力的更高敏感性。ΔcpxAR比野生型菌株对β-内酰胺和氯霉素更敏感，互补恢复了改变的表型。qRT-PCR结果显示，cpxAR突变体中acrB、acrD、eefB外排基因表达的相对变化降低。外膜蛋白质谱的比较表明在敲除背景中的显著差异。凝胶位移分析表明CpxRKP以浓度依赖性方式直接结合ompC KP的启动子区。已知Cpx包膜应激反应系统通过pH值、膜组成和错误折叠蛋白的改变而被激活，并且该系统性研究首次揭示了其直接参与赋予对临床显著抗生素的抗微生物耐药性。本报告中显示的总体结果反映了CpxAR信号系统的多效性作用和高毒力K1血清型K中抗生素耐药组的多样性。pneumoniae NTUH-K2044.
Klebsiella pneumoniae is a Gram-negative, non-motile, facultative anaerobe belonging to the Enterobacteriaceae family of the γ-Proteobacteria class in the phylum Proteobacteria. Multidrug resistant K. pneumoniae have caused major therapeutic problems worldwide due to emergence of extended-spectrum β-lactamase producing strains. Two-component systems serve as a basic stimulus-response coupling mechanism to allow organisms to sense and respond to changes in many different environmental conditions including antibiotic stress. In the present study, we investigated the role of an uncharacterized cpxAR operon in bacterial physiology and antimicrobial resistance by generating isogenic mutant (ΔcpxAR) deficient in the CpxA/CpxR component derived from the hyper mucoidal K1 strain K. pneumoniae NTUH-K2044. The behaviour of ΔcpxAR was determined under hostile conditions, reproducing stresses encountered in the gastrointestinal environment and deletion resulted in higher sensitivity to bile, osmotic and acid stresses. The ΔcpxAR was more susceptible to β-lactams and chloramphenicol than the wild-type strain, and complementation restored the altered phenotypes. The relative change in expression of acrB, acrD, eefB efflux genes were decreased in cpxAR mutant as evidenced by qRT-PCR. Comparison of outer membrane protein profiles indicated a conspicuous difference in the knock out background. Gel shift assays demonstrated direct binding of CpxRKP to promoter region of ompC KP in a concentration dependent manner. The Cpx envelope stress response system is known to be activated by alterations in pH, membrane composition and misfolded proteins, and this systematic investigation reveals its direct involvement in conferring antimicrobial resistance against clinically significant antibiotics for the very first time. Overall results displayed in this report reflect the pleiotropic role of the CpxAR signaling system and diversity of the antibiotic resistome in hyper virulent K1 serotype K. pneumoniae NTUH-K2044.
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