Trade-Offs Between Antibacterial Resistance and Fitness Cost in the Production of Metallo-β-Lactamase by Enteric Bacteria Manifest as Sporadic Emergence of Carbapenem Resistance in a Clinical Setting

Abstract

Meropenem is a clinically important antibacterial reserved for treatment of multi-resistant infections. In meropenem-resistant bacteria of the family Enterobacteriales, 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 Enterobacteriales, 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 Enterobacteriales because of amino acid starvation. 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 a Klebsiella 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.

A novel, magnetic bead-based extraction method for the isolation of antimicrobial resistance genes with a case study in river water in Malawi

“…By contrast, a greater number of ESBL resistance genes were detected post incubation than direct from water filter. There has been an increase in data surrounding the relative fitness costs on bacteria that harbour resistance markers in the absence of selection pressure, notably those associated with large mobile plasmids (Cheung et al, 2021). We hypothesise that the loss here is due to carbapenemases being less stable within bacteria than ESBLs, similar to outcomes observed by Cheung et al (2021).…”

“…There has been an increase in data surrounding the relative fitness costs on bacteria that harbour resistance markers in the absence of selection pressure, notably those associated with large mobile plasmids (Cheung et al, 2021). We hypothesise that the loss here is due to carbapenemases being less stable within bacteria than ESBLs, similar to outcomes observed by Cheung et al (2021). However, more extensive research is needed to both further our understanding of AMR as well as guide laboratory practice.…”

The Carbapenemase BKC-1 from Klebsiella pneumoniae Is Adapted for Translocation by Both the Tat and Sec Translocons

“…Indeed, studies in E. coli showed that the overall assembly rates for virulence factors like FimD and UshC are dependent on how well features in these protein sequences can be handled by the components of the host cell's biosynthetic machinery (74). Similarly, for b-lactamases, a substantial fitness cost of carbapenem resistance has been quantified and linked to amino acid starvation due to codon usage incompatibility and other issues associated with maintaining sufficiently high expression levels of the carbapenemase (75).…”