摘要

多药耐药菌已成为严重威胁人类健康的全球性细菌，结合质粒是导致耐药性快速传播的重要驱动力。尽管抗生素已经被证明选择抗性质粒来适应其新的细菌宿主，或者反之亦然，但是还没有出现一般的进化机制。在这里，我们进行了一项实验进化研究，旨在确定质粒-细菌进化的一般模式。具体来说，我们发现在相同和其他物种中，大的结合抗性质粒与其非结合的小复制子遵循相同的进化轨迹。此外，在单个宿主-质粒对中，三种不同的适应性进化模式导致质粒持久性的增加: I )复制蛋白基因( trfA1 )的突变；ii )通过抗性质粒从编码推定毒素-抗毒素系统的共存质粒获得转座子；iii )宿主的全局转录调节基因fur中的突变。由于这些进化解决方案中的每一个都单独地被证明增加了质粒在其它质粒-宿主对中的持久性，我们的工作指向质粒稳定的共同机制。这些可能成为未来替代药物治疗的目标，以减缓抗生素耐药性的传播。

Multidrug resistant bacterial pathogens have become a serious global human health threat, and conjugative plasmids are important drivers of the rapid spread of resistance to last-resort antibiotics. Whereas antibiotics have been shown to select for adaptation of resistance plasmids to their new bacterial hosts, or vice versa, a general evolutionary mechanism has not yet emerged. Here we conducted an experimental evolution study aimed at determining general patterns of plasmid-bacteria evolution. Specifically, we found that a large conjugative resistance plasmid follows the same evolutionary trajectories as its non-conjugative mini-replicon in the same and other species. Furthermore, within a single host–plasmid pair three distinct patterns of adaptive evolution led to increased plasmid persistence: i) mutations in the replication protein gene (trfA1); ii) the acquisition by the resistance plasmid of a transposon from a co-residing plasmid encoding a putative toxin-antitoxin system; iii) a mutation in the host’s global transcriptional regulator gene fur. Since each of these evolutionary solutions individually have been shown to increase plasmid persistence in other plasmid-host pairs, our work points towards common mechanisms of plasmid stabilization. These could become the targets of future alternative drug therapies to slow down the spread of antibiotic resistance.

https://www.nature.com/articles/s41598-017-04662-0