Trade-offs between antibacterial resistance and fitness cost in the production of metallo-b-lactamases by enteric bacteria manifest as sporadic emergence of carbapenem resistance in a clinical setting

Ching Hei Phoebe Cheung, Mohammed Alorabi, Fergus Hamilton, Yuiko Takebayashi, Oliver Mounsey, Kate J Heesom, Philip B Williams, O Martin Williams, Mahableshwar Albur, Alasdair P MacGowan, Matthew B Avison*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)
67 Downloads (Pure)

Abstract

Meropenem is a clinically important antibacterial reserved for treatment of multi-resistant infections. In meropenem-resistant bacteria of the family Enterobacterales, NDM-1 is considerably more common than IMP-1, despite both metallo-β-lactamases (MBLs) hydrolysing meropenem with almost identical kinetics. We show that blaNDM-1 consistently confers meropenem resistance in wild-type Enterobacterales, but blaIMP-1 does not. The reason is higher blaNDM-1 expression because of its stronger promoter. However, the cost of meropenem resistance is reduced fitness of blaNDM-1 positive Enterobacterales. In parallel, from a clinical case, we identified multiple Enterobacter spp. isolates carrying a plasmid-encoded blaNDM-1 having a modified promoter region. This modification lowered MBL production to a level associated with zero fitness cost but, consequently, the isolates were not meropenem resistant. However, we identified aKlebsiella pneumoniae isolate from this same clinical case carrying the same blaNDM-1 plasmid. This isolate was meropenem resistant despite low-level NDM-1 production because of a ramR mutation, reducing envelope permeability. Overall, therefore, we show how the resistance/fitness trade-off for MBL carriage can be resolved. The result is sporadic emergence of meropenem resistance in a clinical setting.
Original languageEnglish
Article numbere02412-20
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number8
Early online date10 May 2021
DOIs
Publication statusPublished - 16 Jul 2021

Bibliographical note

Funding Information:
This work was funded by grant MR/N013646/1 to M.B.A., O.M.W., A.P.M., and K.J.H. and grant MR/S004769/1 to M.B.A. from the Antimicrobial Resistance Cross Council Initiative supported by the seven UK research councils and the National Institute for Health Research and grant MR/T005408/1 to P.B.W. and M.B.A. from the Medical Research Council. M. Alorabi was supported by a postgraduate scholarship from the Cultural Bureau of the Kingdom of Saudi Arabia. F.H. was supported by a clinical fellowship from the Wellcome Trust. Genome sequencing was provided by MicrobesNG (http://www.microbesng.uk).

Publisher Copyright:
Copyright © 2021 American Society for Microbiology. All Rights Reserved.

Fingerprint

Dive into the research topics of 'Trade-offs between antibacterial resistance and fitness cost in the production of metallo-b-lactamases by enteric bacteria manifest as sporadic emergence of carbapenem resistance in a clinical setting'. Together they form a unique fingerprint.

Cite this