Multicopy plasmids potentiate the evolution of antibiotic resistance in bacteria
Multicopy plasmids potentiate the evolution of antibiotic resistance in bacteria
复制标题
DOI：
10.1038/s41559-016-0010
复制
发表时间：
2017-01-01
影响因子：
16.8
通讯作者：
MacLean, R. Craig
中科院分区：
文献类型：
--
作者：
San Milian, Alvaro;Escudero, Jose Antonio;MacLean, R. Craig
质粒被认为是细菌进化中的关键作用，作为水平基因转移的载体，但质粒作为基因进化的催化剂的作用仍然没有得到探索。我们挑战人口的大肠杆菌携带bla（TEM-1）β-内酰胺酶基因的染色体或多拷贝质粒（19个拷贝/细胞）与头孢他啶浓度增加。该质粒通过增加新TEM-1突变的出现率，从而赋予头孢他啶耐药性，然后由于增加的基因剂量而放大TEM-1突变的作用，从而加速耐药性演变。至关重要的是，这种双重效应对于临床相关耐药性水平的演变是必要的和充分的。随后的进化发生在调节RNA的突变，增加了质粒拷贝数，导致头孢他啶耐药性的边际增加。这些结果揭示了多拷贝质粒作为细菌抗生素耐药性进化催化剂的作用。
Plasmids are thought to play a key role in bacterial evolution by acting as vehicles for horizontal gene transfer, but the role of plasmids as catalysts of gene evolution remains unexplored. We challenged populations of Escherichia coli carrying the bla(TEM-1) beta-lactamase gene on either the chromosome or a multicopy plasmid (19 copies per cell) with increasing concentrations of ceftazidime. The plasmid accelerated resistance evolution by increasing the rate of appearance of novel TEM-1 mutations, thereby conferring resistance to ceftazidime, and then by amplifying the effect of TEM-1 mutations due to the increased gene dosage. Crucially, this dual effect was necessary and sufficient for the evolution of clinically relevant levels of resistance. Subsequent evolution occurred by mutations in a regulatory RNA that increased the plasmid copy number, resulting in marginal gains in ceftazidime resistance. These results uncover a role for multicopy plasmids as catalysts for the evolution of antibiotic resistance in bacteria.