Clinically Relevant Plasmid-Host Interactions Indicate that Transcriptional and Not Genomic Modifications Ameliorate Fitness Costs of Klebsiella pneumoniae Carbapenemase-Carrying Plasmids.
Clinically Relevant Plasmid-Host Interactions Indicate that Transcriptional and Not Genomic Modifications Ameliorate Fitness Costs of Klebsiella pneumoniae Carbapenemase-Carrying Plasmids.
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DOI：
10.1128/mbio.02303-17
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发表时间：
2018-04-24
期刊：
影响因子：
6.4
通讯作者：
Piddock LJV
中科院分区：
文献类型：
--
作者：
Buckner MMC;Saw HTH;Osagie RN;McNally A;Ricci V;Wand ME;Woodford N;Ivens A;Webber MA;Piddock LJV
抗菌素耐药性(AMR)在全球的迅速传播在很大程度上是由于可移动的遗传元件，如质粒。它们使人对关键药物产生耐药性，包括超广谱β-内酰胺类药物、碳青霉烯类和粘菌素。大型、复杂的耐药质粒与它们的宿主细菌一起进化。然而，许多关于质粒-宿主进化的研究都集中在实验室适应的细菌宿主中的小而简单的实验室质粒上。这些研究和其他研究都记录了宿主和质粒基因的突变，这些突变发生在引入质粒后，以改善质粒携带的适合性成本。我们在这里描述了一个大的AMR质粒(PKpQIL)的两个自然发生的变体对一个全球成功的病原体的影响。在我们的研究中，pKpQIL质粒导入后，其自然宿主肺炎克雷伯菌的编码区序列没有变化。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AMR质粒的获得。我们假设这足以改善相关的适合性成本，因为pKpQIL的载体没有选择压力。去除选择压力(例如，抗菌剂暴露)会由于细菌适合性成本而导致质粒丢失的教条并不适用于所有的质粒/宿主组合。我们还表明，pKpQIL影响肺炎克雷伯菌形成生物膜的能力，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，并揭示了与实验室适应的质粒和菌株的研究结果显著不同。抗菌素耐药性是社会面临的一个严重问题。许多赋予抗药性的基因可以通过可移动的遗传元件在细菌之间共享，例如质粒。我们的工作表明，当两个临床相关的AMR质粒进入它们的自然宿主细菌时，基因表达会发生变化，而不是基因编码序列的变化。基因表达的这些变化改善了携带这些AMR质粒的潜在适合性成本。与此相一致的是，质粒在它们的自然宿主中是稳定的，并且在没有选择压力的情况下不会丢失。我们还表明，更好地了解耐药质粒对基本病原体生物学的影响，包括生物膜的形成，对于抗击耐药感染至关重要。
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, Klebsiella pneumoniae. 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 K. pneumoniae 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.