Identification of 76 novel B1 metallo-β-lactamases through large-scale screening of genomic and metagenomic data.
Identification of 76 novel B1 metallo-β-lactamases through large-scale screening of genomic and metagenomic data.
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DOI：
10.1186/s40168-017-0353-8
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发表时间：
2017-10-12
期刊：
影响因子：
15.5
通讯作者：
Kristiansson E
中科院分区：
文献类型：
--
作者：
Berglund F;Marathe NP;Österlund T;Bengtsson-Palme J;Kotsakis S;Flach CF;Larsson DGJ;Kristiansson E
金属β-内酰胺酶是一种细菌酶，可以抵抗碳青霉烯类抗生素，而碳青霉烯类抗生素是最有效的一类抗生素。这些酶通常编码在可移动的遗传元件上，再加上它们广泛的底物谱和缺乏临床有用的抑制剂，使它们成为一类特别有问题的抗生素耐药性决定因素。我们假设存在大量未知的金属β-内酰胺酶，其中一些可能会传播给病原体，从而威胁到公众健康。本研究的目的是鉴定新的B1类金属β-内酰胺酶，这是这些酶在临床上最重要的亚类。基于一种新的计算方法，利用优化的隐马尔可夫模型，我们分析了超过10,000个细菌基因组和质粒以及超过5tb的宏基因组数据，以鉴定新的金属β-内酰胺酶基因。总共预测了76个新基因，形成了59个以前未描述的金属β-内酰胺酶基因家族。实验证实，在21个测试基因中，有18个在大肠杆菌宿主中具有水解亚胺培南的能力。两个新的B1金属β-内酰胺酶基因在其活性位点含有非典型的锌结合基序，这是以前在金属β-内酰胺酶中描述过的。系统发育分析表明，B1金属β-内酰胺酶根据其进化起源可分为五大类群。我们的研究结果还表明，除了一种外，所有先前表征的移动B1 β-内酰胺酶都可能起源于存在于希瓦氏菌和其他变形菌物种中的染色体基因。这项研究将已知的B1金属β内酰胺酶的数量增加了一倍以上。这些发现进一步阐明了这类重要抗生素耐药基因的多样性和进化史，并为我们将来在临床中可能面临的一些挑战做好了准备。本文的在线版本（10.1186/s40168-017-0353-8）包含补充材料，仅供授权用户使用。
Metallo-β-lactamases are bacterial enzymes that provide resistance to carbapenems, the most potent class of antibiotics. These enzymes are commonly encoded on mobile genetic elements, which, together with their broad substrate spectrum and lack of clinically useful inhibitors, make them a particularly problematic class of antibiotic resistance determinants. We hypothesized that there is a large and unexplored reservoir of unknown metallo-β-lactamases, some of which may spread to pathogens, thereby threatening public health. The aim of this study was to identify novel metallo-β-lactamases of class B1, the most clinically important subclass of these enzymes. Based on a new computational method using an optimized hidden Markov model, we analyzed over 10,000 bacterial genomes and plasmids together with more than 5 terabases of metagenomic data to identify novel metallo-β-lactamase genes. In total, 76 novel genes were predicted, forming 59 previously undescribed metallo-β-lactamase gene families. The ability to hydrolyze imipenem in an Escherichia coli host was experimentally confirmed for 18 of the 21 tested genes. Two of the novel B1 metallo-β-lactamase genes contained atypical zinc-binding motifs in their active sites, which were previously undescribed for metallo-β-lactamases. Phylogenetic analysis showed that B1 metallo-β-lactamases could be divided into five major groups based on their evolutionary origin. Our results also show that, except for one, all of the previously characterized mobile B1 β-lactamases are likely to have originated from chromosomal genes present in Shewanella spp. and other Proteobacterial species. This study more than doubles the number of known B1 metallo-β-lactamases. The findings have further elucidated the diversity and evolutionary history of this important class of antibiotic resistance genes and prepare us for some of the challenges that may be faced in clinics in the future. The online version of this article (10.1186/s40168-017-0353-8) contains supplementary material, which is available to authorized users.
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影响因子：
14.9
作者：
Clark K;Karsch-Mizrachi I;Lipman DJ;Ostell J;Sayers EW
通讯作者：
Sayers EW
影响因子：
4.4
作者：
Donato, Justin J.;Moe, Luke A.;Handelsman, Jo
通讯作者：
Handelsman, Jo
DOI：
10.1126/science.1220761
发表时间：
2012-08-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Forsberg KJ;Reyes A;Wang B;Selleck EM;Sommer MO;Dantas G
通讯作者：
Dantas G
影响因子：
4.4
作者：
Boulund F;Berglund F;Flach CF;Bengtsson-Palme J;Marathe NP;Larsson DGJ;Kristiansson E
通讯作者：
Kristiansson E
影响因子：
1.7
作者：
Bankevich, Anton;Nurk, Sergey;Pevzner, Pavel A.
通讯作者：
Pevzner, Pavel A.