Trade-Offs Between Antibacterial Resistance and Fitness Cost in the Production of Metallo-β-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

5 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
JournalAntimicrobial Agents and Chemotherapy
Early online date10 May 2021
DOIs
Publication statusE-pub ahead of print - 10 May 2021

Fingerprint

Dive into the research topics of 'Trade-Offs Between Antibacterial Resistance and Fitness Cost in the Production of Metallo-β-Lactamases by Enteric Bacteria Manifest as Sporadic Emergence of Carbapenem Resistance in a Clinical Setting'. Together they form a unique fingerprint.

Cite this