Identification of 76 novel B1 metallo-β-lactamases through large-scale screening of genomic and metagenomic data

作者：Fanny Berglund, Nachiket P. Marathe, Tobias Österlund, Johan Bengtsson‐Palme, Stathis D. Kotsakis, Carl‐Fredrik Flach, D. G. Joakim Larsson, Erik Kristiansson · 发表于：Microbiome · 年份：2017 · DOI：10.1186/s40168-017-0353-8 · 被引用次数：106 · 研究领域：Antibiotic Resistance in Bacteria、Chromium effects and bioremediation、Bacterial biofilms and quorum sensing

BACKGROUND: 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. RESULTS: 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 ...