Comprehensive Genome Analysis of Carbapenemase-Producing Enterobacter spp.: New Insights into Phylogeny, Population Structure, and Resistance Mechanisms.
Comprehensive Genome Analysis of Carbapenemase-Producing Enterobacter spp.: New Insights into Phylogeny, Population Structure, and Resistance Mechanisms.
复制标题
碳青霉酶产生肠杆菌属的全面基因组分析：对系统发育，种群结构和耐药机制的新见解。
DOI：
10.1128/mbio.02093-16
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发表时间：
2016-12-13
期刊：
影响因子：
6.4
通讯作者：
Kreiswirth BN
中科院分区：
文献类型：
--
作者：
Chavda KD;Chen L;Fouts DE;Sutton G;Brinkac L;Jenkins SG;Bonomo RA;Adams MD;Kreiswirth BN
关于肠杆菌属的基因组结构的知识，第二种最普遍的产碳青霉烯酶肠杆菌科细菌仍然有限。在这里，我们对来自不同地理区域的97种临床肠杆菌属分离株进行了测序，这些肠杆菌属分离株对碳青霉烯类抗生素敏感和耐药，以破译碳青霉烯类抗生素耐药的分子起源，并了解这些新兴和耐药病原体不断变化的系统发育史。在碳青霉烯类耐药分离株中，30株具有blaKPC-2，40株具有blaKPC-3，2株具有blaKPC-4，2株具有blaNDM-1。23株分离株对碳青霉烯类抗生素敏感。六个基因组测序完成，其大小范围从4.6到5.1 Mbp。系统基因组学分析将这些基因组中的96个、从NCBI GenBank下载的另外351个肠杆菌属基因组和6个新测序的模式菌株置于19个肠杆菌基因组群中-在阴沟肠杆菌复合体和产气肠杆菌中的18个群（A至R）。这些耐药肠杆菌属的分子进化轨迹的不同机制。揭示了，包括抗生素抗性质粒的收购，随后的克隆传播，blaKPC-窝藏质粒之间的水平转移不同的大肠杆菌基因组组，和重复转座的blaKPC基因在不同的质粒骨架。组A，其中包括多位点序列类型171（ST 171），是最常见的（23%的分离株）。基因组分析表明，ST 171菌株从一个共同的祖先进化而来，形成了两个不同的主要集群，每个获得独特的blaKPC-窝藏质粒，然后克隆扩增。这里提供的数据代表了首次对碳青霉烯类耐药肠杆菌属细菌的基因组询问以及抗生素耐药性和质粒鉴别之间关系的全面研究，证明了该属中驱动抗生素抗性的分子机制的遗传多样性和复杂性。肠杆菌属，尤其是产碳青霉烯酶的肠杆菌属，已经成为医院感染的临床重要原因。然而，关于碳青霉烯类抗生素耐药性在该属中的分布，仅有有限的信息可用。由于分型方法不明确和分类不精确，导致肠杆菌属菌株的错误鉴定，从而加剧了这一问题。在这项研究中，我们使用了一种基于全基因组的比较系统发育方法，（i）重新审视和重新定义肠杆菌属，（ii）阐明携带碳青霉烯酶的肺炎克雷伯菌肠杆菌属的出现和进化。通过对447株测序菌株的基因组分析，我们对这一复杂属内的物种命名有了更好的理解，并确定了驱动碳青霉烯类耐药性分子进化的多种机制。这项研究的发现提供了一个坚实的基因组框架，将作为分子诊断学未来发展和支持药物发现计划的重要资源。
Knowledge regarding the genomic structure of Enterobacter spp., the second most prevalent carbapenemase-producing Enterobacteriaceae, remains limited. Here we sequenced 97 clinical Enterobacter species isolates that were both carbapenem susceptible and resistant from various geographic regions to decipher the molecular origins of carbapenem resistance and to understand the changing phylogeny of these emerging and drug-resistant pathogens. Of the carbapenem-resistant isolates, 30 possessed blaKPC-2, 40 had blaKPC-3, 2 had blaKPC-4, and 2 had blaNDM-1. Twenty-three isolates were carbapenem susceptible. Six genomes were sequenced to completion, and their sizes ranged from 4.6 to 5.1 Mbp. Phylogenomic analysis placed 96 of these genomes, 351 additional Enterobacter genomes downloaded from NCBI GenBank, and six newly sequenced type strains into 19 phylogenomic groups—18 groups (A to R) in the Enterobacter cloacae complex and Enterobacter aerogenes. Diverse mechanisms underlying the molecular evolutionary trajectory of these drug-resistant Enterobacter spp. were revealed, including the acquisition of an antibiotic resistance plasmid, followed by clonal spread, horizontal transfer of blaKPC-harboring plasmids between different phylogenomic groups, and repeated transposition of the blaKPC gene among different plasmid backbones. Group A, which comprises multilocus sequence type 171 (ST171), was the most commonly identified (23% of isolates). Genomic analysis showed that ST171 isolates evolved from a common ancestor and formed two different major clusters; each acquiring unique blaKPC-harboring plasmids, followed by clonal expansion. The data presented here represent the first comprehensive study of phylogenomic interrogation and the relationship between antibiotic resistance and plasmid discrimination among carbapenem-resistant Enterobacter spp., demonstrating the genetic diversity and complexity of the molecular mechanisms driving antibiotic resistance in this genus. Enterobacter spp., especially carbapenemase-producing Enterobacter spp., have emerged as a clinically significant cause of nosocomial infections. However, only limited information is available on the distribution of carbapenem resistance across this genus. Augmenting this problem is an erroneous identification of Enterobacter strains because of ambiguous typing methods and imprecise taxonomy. In this study, we used a whole-genome-based comparative phylogenetic approach to (i) revisit and redefine the genus Enterobacter and (ii) unravel the emergence and evolution of the Klebsiella pneumoniae carbapenemase-harboring Enterobacter spp. Using genomic analysis of 447 sequenced strains, we developed an improved understanding of the species designations within this complex genus and identified the diverse mechanisms driving the molecular evolution of carbapenem resistance. The findings in this study provide a solid genomic framework that will serve as an important resource in the future development of molecular diagnostics and in supporting drug discovery programs.