摘要
      由抗生素抗性基因（ARGs）组成的模块两侧有反向重复的Xer特异性重组位点，被认为是促进水平传播的可移动遗传元件。较不常见的是，质粒中存在移动模块，这有助于pdif介导的ARGs转移。在这里，已经在pdif位点对中发现了许多ARGs和毒素抗毒素基因。然而，目前尚不清楚这种明显的遗传迁移的机制，也缺乏关于pdif介导的ARGs转移到大多数细菌属的研究。我们基于一种名为PdifSM的算法开发了网络服务器pdifFinder，该算法可以预测细菌基因组中不同的pdif-ARGs模块。使用由来自717个物种的近3.2万个质粒组成的测试集，PdifSM从含有带有ARGs的pdif位点的各种细菌中鉴定了481个质粒。我们发现来自不同属的28个碱基长的元件具有明确的碱基偏好。我们获得的数据表明，XerCD-dif位点特异性重组机制可能具有进化适应性，以促进pdif介导的ARGs转移。通过对重复的pdif ARGs模块的多序列比对和进化分析，我们发现pdif位点允许ARGs的种间转移，也可以跨不同属转移。pdif位点的突变产生了介导多药耐药性的不同模块阵列，因为这些模块包含不同数量的不同ARG、插入序列和其他功能基因。pdif-ARGs模块的鉴定和对ARGs共转移机制的研究将有助于我们理解并可能控制MDR细菌在临床环境中的传播。pdifFinder代码、独立软件包和教程说明可在https://github.com/mjshao06/pdifFinder.
Abstract
Modules consisting of antibiotic resistance genes (ARGs) flanked by inverted repeat Xer-specific recombination sites were thought to be mobile genetic elements that promote horizontal transmission. Less frequently, the presence of mobile modules in plasmids, which facilitate a pdif-mediated ARGs transfer, has been reported. Here, numerous ARGs and toxin-antitoxin genes have been found in pdif site pairs. However, the mechanisms underlying this apparent genetic mobility is currently not understood, and the studies relating to pdif-mediated ARGs transfer onto most bacterial genera are lacking. We developed the web server pdifFinder based on an algorithm called PdifSM that allows the prediction of diverse pdif-ARGs modules in bacterial genomes. Using test set consisting of almost 32 thousand plasmids from 717 species, PdifSM identified 481 plasmids from various bacteria containing pdif sites with ARGs. We found 28-bp-long elements from different genera with clear base preferences. The data we obtained indicate that XerCD-dif site-specific recombination mechanism may have evolutionary adapted to facilitate the pdif-mediated ARGs transfer. Through multiple sequence alignment and evolutionary analyses of duplicated pdif-ARGs modules, we discovered that pdif sites allow an interspecies transfer of ARGs but also across different genera. Mutations in pdif sites generate diverse arrays of modules which mediate multidrug-resistance, as these contain variable numbers of diverse ARGs, insertion sequences and other functional genes. The identification of pdif-ARGs modules and studies focused on the mechanism of ARGs co-transfer will help us to understand and possibly allow controlling the spread of MDR bacteria in clinical settings. The pdifFinder code, standalone software package and description with tutorials are available at https://github.com/mjshao06/pdifFinder.

https://academic.oup.com/bib/article-abstract/24/1/bbac521/6873868?login=false