Evolutionary responses to acquiring a multidrug resistance plasmid are dominated by metabolic functions across diverse Escherichia coli lineages
Evolutionary responses to acquiring a multidrug resistance plasmid are dominated by metabolic functions across diverse Escherichia coli lineages
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获得多药耐药质粒的进化反应由不同大肠杆菌谱系的代谢功能主导
DOI：
10.1101/2022.07.22.501110
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Carrilero L
中科院分区：
文献类型：
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作者：
Carrilero L
多药耐药(MDR)质粒导致抗生素耐药性在细菌谱系之间传播。获得MDR质粒对适应性和细胞过程的直接影响因细菌谱系而异，但使MDR质粒的基因组整合发生变化的进化过程如何变化尚不清楚，特别是在临床病原体中。利用实验进化了约700代的不同的大肠杆菌谱系，我们表明，获得MDR质粒pLL35的进化反应由影响代谢和调节功能的染色体突变主导，具有菌株特异性和共同的突变靶点。其中一些功能的表达，如无氧代谢，已知在获得pLL35后会发生变化。与驻留的移动遗传元件，特别是几个IS元件的相互作用，加强了平行突变，包括插入与其上调相关的HN上游，以及质粒编码的超广谱β-内酰胺酶基因的下调。质粒平行突变针对的是接合相关基因，这些基因的表达在进化克隆中也普遍下调。除了在水平基因转移中的作用外，质粒还可以是塑造细菌染色体进化和核心细胞功能的重要选择性力量。重要的载体推动抗菌素耐药基因在细菌基因组之间的传播。然而，允许不同细菌基因组同化质粒的进化过程知之甚少，特别是在临床病原体中。利用不同的大肠杆菌谱系和临床多药耐药质粒的实验进化，我们表明，尽管质粒驱动每个谱系的独特进化路径，但在由代谢功能主导的跨谱系突变所针对的功能中存在令人惊讶的收敛程度。值得注意的是，在自然界中，这些相同的代谢功能在MDR谱系中显示出更高的进化率，在某些情况下，如厌氧代谢，它们的表达直接由质粒操纵。与驻留在基因组中的其他移动元件的相互作用通过扰乱它们插入的基因和调控序列来加速适应。除了它们在水平基因转移中的作用外，质粒还是推动细菌基因组和核心细胞功能进化的重要选择力量。
Multidrug resistance (MDR) plasmids drive the spread of antibiotic resistance between bacterial lineages. The immediate impact of MDR plasmid acquisition on fitness and cellular processes varies among bacterial lineages, but how the evolutionary processes enabling the genomic integration of MDR plasmids vary is less well understood, particularly in clinical pathogens. Using diverse Escherichia coli lineages experimentally evolved for ~700 generations, we show that the evolutionary response to gaining the MDR plasmid pLL35 was dominated by chromosomal mutations affecting metabolic and regulatory functions, with both strain-specific and shared mutational targets. The expression of several of these functions, such as anaerobic metabolism, is known to be altered upon acquisition of pLL35. Interactions with resident mobile genetic elements, notably several IS-elements, potentiated parallel mutations, including insertions upstream ofhnsthat were associated with its upregulation and the downregulation of the plasmid-encoded extended-spectrum beta-lactamase gene. Plasmid parallel mutations targeted conjugation-related genes, whose expression was also commonly downregulated in evolved clones. Beyond their role in horizontal gene transfer, plasmids can be an important selective force shaping the evolution of bacterial chromosomes and core cellular functions.IMPORTANCEPlasmids drive the spread of antimicrobial resistance genes between bacterial genomes. However, the evolutionary processes allowing plasmids to be assimilated by diverse bacterial genomes are poorly understood, especially in clinical pathogens. Using experimental evolution with diverse E. coli lineages and a clinical multidrug resistance plasmid, we show that although plasmids drove unique evolutionary paths per lineage, there was a surprising degree of convergence in the functions targeted by mutations across lineages, dominated by metabolic functions. Remarkably, these same metabolic functions show higher evolutionary rates in MDR-lineages in nature and in some cases, like anaerobic metabolism, their expression is directly manipulated by the plasmid. Interactions with other mobile elements resident in the genomes accelerated adaptation by disrupting genes and regulatory sequences that they inserted into. Beyond their role in horizontal gene transfer, plasmids are an important selective force driving the evolution of bacterial genomes and core cellular functions.