Tetracyclines are broad-spectrum antibiotics used to prevent or treat a variety of bacterial infections. Resistance is often mediated through mobile resistance genes, which encode one of the three main mechanisms: active efflux, ribosomal target protection or enzymatic degradation. In the last few decades, a large number of new tetracycline-resistance genes have been discovered in clinical settings. These genes are hypothesized to originate from environmental and commensal bacteria, but the diversity of tetracycline-resistance determinants that have not yet been mobilized into pathogens is unknown. In this study, we aimed to characterize the potential tetracycline resistome by screening genomic and metagenomic data for novel resistance genes. By using probabilistic models, we predicted 1254 unique putative tetracycline resistance genes, representing 195 gene families (<70 % amino acid sequence identity), whereof 164 families had not been described previously. Out of 17 predicted genes selected for experimental verification, 7 induced a resistance phenotype in an Escherichia coli host. Several of the predicted genes were located on mobile genetic elements or in regions that indicated mobility, suggesting that they easily can be shared between bacteria. Furthermore, phylogenetic analysis indicated several events of horizontal gene transfer between bacterial phyla. Our results also suggested that acquired efflux pumps originate from proteobacterial species, while ribosomal protection genes have been mobilized from Firmicutes and Actinobacteria . This study significantly expands the knowledge of known and putatively novel tetracycline resistance genes, their mobility and evolutionary history. The study also provides insights into the unknown resistome and genes that may be encountered in clinical settings in the future.

中文翻译：

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基因组和宏基因组数据的综合筛选揭示了四环素抗性基因的多样性

四环素是广谱抗生素，用于预防或治疗各种细菌感染。抗性通常通过移动抗性基因介导，这些基因编码三种主要机制之一：主动外排、核糖体靶标保护或酶促降解。在过去的几十年中，在临床环境中发现了大量新的四环素抗性基因。假设这些基因来自环境和共生细菌，但尚未动员到病原体中的四环素抗性决定簇的多样性尚不清楚。在这项研究中，我们旨在通过筛选新抗性基因的基因组和宏基因组数据来表征潜在的四环素抗性组。通过使用概率模型，我们预测了 1254 个独特的推定四环素抗性基因，代表 195 个基因家族（<70% 氨基酸序列同一性），其中 164 个家族以前未曾被描述过。在选择用于实验验证的 17 个预测基因中，7 个在 大肠杆菌 宿主。几个预测的基因位于可移动的遗传元件上或位于表明可移动的区域，这表明它们很容易在细菌之间共享。此外，系统发育分析表明细菌门之间的水平基因转移的几个事件。我们的研究结果还表明，获得性外排泵源自变形菌种，而核糖体保护基因则来自厚壁菌门和放线菌。这项研究显着扩展了对已知和推定的新型四环素抗性基因、它们的移动性和进化历史的认识。该研究还提供了对未来临床环境中可能遇到的未知耐药组和基因的见解。