Clinically relevant plasmid-host interactions indicate that transcriptional and not genomic modifications ameliorate fitness costs of Klebsiella pneumoniae carbapenemase-carrying plasmids

Michelle M.C. Buckner, Howard T.H. Saw, Rachael N. Osagie, Alan McNally, Vito Ricci, Matthew E. Wand, Neil Woodford, Alasdair Ivens, Mark A. Webber, Laura J.V. Piddock*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

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. IMPORTANCE 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.

Original languageEnglish
Article numbere02303-17
JournalmBio
Volume9
Issue number2
DOIs
Publication statusPublished - 1 Mar 2018

Bibliographical note

Funding Information:
We are grateful to Edward Bevan and Blaise Pascal Bougnom for critical reading of the manuscript and to members of ARG for constructive discussions. An Elite Doctoral Researcher scholarship, University of Birmingham, was awarded to H.T.H.S. and L.J.V.P. M.M.C.B. was funded in part by an AXA Research Fund fellowship, a fellowship from the Wellcome Trust Institutional Strategic Support Fund, and a Medical Research Council grant to L.J.V.P. R.N.O. was funded by a British Commonwealth fellowship. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. M.M.C.B., H.T.H.S., R.N.O., A.M., V.R., M.E.W., A.I., M.A.W., and L.J.V.P. have no conflicts to declare. N.W. has no personal conflicts to declare, but the AMRHAI Reference Unit of Public Health England (PHE) has received financial support for conference attendance, lectures, research projects, or contracted evaluations from numerous sources, including the following: Accelerate Diagnostics; Achaogen Inc.; Allecra Therapeutics; Amplex; AstraZeneca UK Ltd.; AusDiagnostics; Basilea Pharmaceutica; Becton Dickinson Diagnostics; bioMérieux; Bio-Rad Laboratories; The BSAC; Cepheid; Check-Points B.V.; Cubist Pharmaceuticals; the UK Department of Health; Enigma Diagnostics; UK Food Standards Agency; GlaxoSmithKline Services Ltd.; Henry Stewart Talks; IHMA Ltd.; Innovate UK; Kalidex Pharmaceuticals; Melinta Therapeutics; Merck Sharpe & Dohme Corp.; Meiji Seika Pharma Co., Ltd.; Mobidiag; Momentum Biosciences Ltd.; Nordic Pharma Ltd.; Norgine Pharmaceuticals; Rempex Pharmaceuticals Ltd.; Roche; Rokitan Ltd.; Shionogi & Co. Ltd.; Smith & Nephew UK Ltd.; Trius Therapeutics; VenatoRx Pharmaceuticals; and Wockhardt Ltd. L.J.V.P. conceived the project. M.M.C.B., H.T.H.S., and L.J.V.P. designed the experiments. M.M.C.B., H.T.H.S., R.N.O., and M.A.W. carried out the experiments. M.M.C.B., H.T.H.S., M.A.W., M.E.W., N.W., A.I., V.R., A.M., and L.J.V.P. performed the data analysis. All of us contributed to writing the article. L.J.V.P. oversaw the work.

Funding Information:
An Elite Doctoral Researcher scholarship, University of Birmingham, was awarded to H.T.H.S. and L.J.V.P. M.M.C.B. was funded in part by an AXA Research Fund fellowship, a fellowship from the Wellcome Trust Institutional Strategic Support Fund, and a Medical Research Council grant to L.J.V.P. R.N.O. was funded by a British Commonwealth fellowship. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Publisher Copyright:
© 2018 Buckner et al.

Keywords

  • Fitness
  • Genome
  • Klebsiella pneumoniae carbapenemase (KPC)
  • PkpQIL
  • Plasmid
  • Transcriptome

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