Step-Wise Increase in Tigecycline Resistance in Klebsiella pneumoniae Associated with Mutations in ramR, lon and rpsJ.
Step-Wise Increase in Tigecycline Resistance in Klebsiella pneumoniae Associated with Mutations in ramR, lon and rpsJ.
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肺炎克雷伯菌替加环素耐药性逐步增加与 ramR、lon 和 rpsJ 突变相关
DOI：
10.1371/journal.pone.0165019
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hua X
中科院分区：
文献类型：
--
作者：
Fang L;Chen Q;Shi K;Li X;Shi Q;He F;Zhou J;Yu Y;Hua X
肺炎克雷伯菌是一种革兰氏阴性菌，可引起多种疾病，包括肺炎和尿路感染。多药耐药性的增加使这些细菌感染的治疗复杂化，尽管替加环素显示出对广泛细菌的活性，但耐药菌株已经出现。在这项研究中，对两种临床菌株和六种实验室进化菌株的全基因组进行了测序，以确定与替加环素耐药性相关的假定突变。7株替加环素耐药菌株中，7株（100%）发生ramR突变，5株（71.4%）发生lon突变，1株（14.2%）发生ramA突变，1株（14.2%）发生rpsJ突变。在实验室进化的菌株中观察到较高的适应成本，而在临床菌株中则没有。转录组分析表明，在所有的替加环素耐药菌株中，ramR操纵子和acrA都有高表达。与野生型和临床菌株相比，实验室进化菌株的氮代谢相关基因被诱导，这种氮代谢的差异反映了实验室进化菌株与临床菌株之间的差异。互补实验表明，野生型ramR和lon基因均能部分恢复肺炎克雷伯菌对替加环素的敏感性。我们认为，这篇论文描述了肺炎克雷伯菌长突变体的第一个结构，这证实了它与替加环素耐药性的关联。我们的研究结果说明了ramR操纵子、lon和rpsJ基因在肺炎克雷伯菌对替加环素的耐药性中的重要性。
Klebsiella pneumoniae is a gram-negative bacterium that causes numerous diseases, including pneumonia and urinary tract infections. An increase in multidrug resistance has complicated the treatment of these bacterial infections, and although tigecycline shows activity against a broad spectrum of bacteria, resistant strains have emerged. In this study, the whole genomes of two clinical and six laboratory-evolved strains were sequenced to identify putative mutations related to tigecycline resistance. Of seven tigecycline-resistant strains, seven (100%) had ramR mutations, five (71.4%) had lon mutations, one (14.2%) had a ramA mutation, and one (14.2%) had an rpsJ mutation. A higher fitness cost was observed in the laboratory-evolved strains but not in the clinical strains. A transcriptome analysis demonstrated high expression of the ramR operon and acrA in all tigecycline-resistant strains. Genes involved in nitrogen metabolism were induced in the laboratory-evolved strains compared with the wild-type and clinical strains, and this difference in nitrogen metabolism reflected the variation between the laboratory-evolved and the clinical strains. Complementation experiments showed that both the wild-type ramR and the lon genes could partially restore the tigecycline sensitivity of K. pneumoniae. We believe that this manuscript describes the first construct of a lon mutant in K. pneumoniae, which allowed confirmation of its association with tigecycline resistance. Our findings illustrate the importance of the ramR operon and the lon and rpsJ genes in K. pneumoniae resistance to tigecycline.
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DOI：
10.1093/jac/dkv486
发表时间：
2016-05
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
--
作者：
Linkevicius M;Anderssen JM;Sandegren L;Andersson DI
通讯作者：
Andersson DI
影响因子：
11.8
作者：
Noskin, GA
通讯作者：
Noskin, GA
影响因子：
4.9
作者：
Nielsen, Lindsey E.;Snesrud, Erik C.;Lesho, Emil P.
通讯作者：
Lesho, Emil P.
影响因子：
5.2
作者：
Linkevicius, Marius;Sandegren, Linus;Andersson, Dan I.
通讯作者：
Andersson, Dan I.
影响因子：
4.5
作者：
Braykov, Nikolay P.;Eber, Michael R.;Laxminarayan, Ramanan
通讯作者：
Laxminarayan, Ramanan