Antimicrobials Research Group, Institute of Microbiology & Infection, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Institute of Microbiology and Infection, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
mBio. 2018 Apr 24;9(2):e02303-17. doi: 10.1128/mBio.02303-17.
The rapid dissemination of antimicrobial resistance (AMR) around the globe is largely due to mobile genetic elements, such as plasmids. They confer resistance to critically important drugs, including extended-spectrum beta-lactams, carbapenems, and colistin. Large, complex resistance plasmids have evolved alongside their host bacteria. However, much of the research on plasmid-host evolution has focused on small, simple laboratory plasmids in laboratory-adapted bacterial hosts. These and other studies have documented mutations in both host and plasmid genes which occur after plasmid introduction to ameliorate fitness costs of plasmid carriage. We describe here the impact of two naturally occurring variants of a large AMR plasmid (pKpQIL) on a globally successful pathogen. In our study, after pKpQIL plasmid introduction, no changes in coding domain sequences were observed in their natural host, However, significant changes in chromosomal and plasmid gene expression may have allowed the bacterium to adapt to the acquisition of the AMR plasmid. We hypothesize that this was sufficient to ameliorate the associated fitness costs of plasmid carriage, as pKpQIL plasmids were maintained without selection pressure. The dogma that removal of selection pressure (e.g., antimicrobial exposure) results in plasmid loss due to bacterial fitness costs is not true for all plasmid/host combinations. We also show that pKpQIL impacted the ability of to form a biofilm, an important aspect of virulence. This study used highly relevant models to study the interaction between AMR plasmids and pathogens and revealed striking differences from results of studies done on laboratory-adapted plasmids and strains. Antimicrobial resistance is a serious problem facing society. Many of the genes that confer resistance can be shared between bacteria through mobile genetic elements, such as plasmids. Our work shows that when two clinically relevant AMR plasmids enter their natural host bacteria, there are changes in gene expression, rather than changes to gene coding sequences. These changes in gene expression ameliorate the potential fitness costs of carriage of these AMR plasmids. In line with this, the plasmids were stable within their natural host and were not lost in the absence of selective pressure. We also show that better understanding of the impact of resistance plasmids on fundamental pathogen biology, including biofilm formation, is crucial for fighting drug-resistant infections.
全球范围内，抗生素耐药性（AMR）的迅速传播在很大程度上是由于移动遗传元件，如质粒。它们使对抗生素至关重要的药物产生耐药性，包括广谱β-内酰胺类、碳青霉烯类和黏菌素。大型复杂的耐药质粒与它们的宿主细菌一起进化。然而，质粒-宿主进化的大部分研究都集中在实验室适应的细菌宿主中的小型、简单的实验室质粒上。这些和其他研究记录了质粒引入后宿主和质粒基因的突变，这些突变发生是为了减轻质粒携带的适应性成本。我们在这里描述了一种大型 AMR 质粒（pKpQIL）的两种自然发生的变体对一种全球成功的病原体的影响。在我们的研究中，pKpQIL 质粒引入后，其天然宿主中没有观察到编码结构域序列的变化。然而，染色体和质粒基因表达的显著变化可能使细菌能够适应获得 AMR 质粒。我们假设这足以减轻与携带质粒相关的适应性成本，因为在没有选择压力的情况下，pKpQIL 质粒得以维持。去除选择压力（例如，抗生素暴露）会导致质粒因细菌适应性成本而丢失的教条并不适用于所有质粒/宿主组合。我们还表明，pKpQIL 影响了形成生物膜的能力，这是毒力的一个重要方面。这项研究使用了高度相关的模型来研究 AMR 质粒和病原体之间的相互作用，结果与在实验室适应的质粒和菌株上进行的研究结果明显不同。抗生素耐药性是社会面临的一个严重问题。许多赋予耐药性的基因可以通过移动遗传元件（如质粒）在细菌之间共享。我们的工作表明，当两种临床相关的 AMR 质粒进入其天然宿主细菌时，会发生基因表达的变化，而不是基因编码序列的变化。这些基因表达的变化减轻了携带这些 AMR 质粒的潜在适应性成本。与此一致的是，在没有选择压力的情况下，这些质粒在其天然宿主中稳定存在，并且不会丢失。我们还表明，更好地了解耐药质粒对包括生物膜形成在内的基本病原体生物学的影响，对于对抗耐药性感染至关重要。
