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.

Cheung, C. H. P.; Alorabi, M.; Hamilton, F.; Takebayashi, Y.; Mounsey, O.; Heesom, K. J.; Williams, P. B.; Williams, M.; Albur, M.; MacGowan, A. P.; Avison, M. B.

doi:10.1101/2020.10.24.353581

bioRxiv · 10.1101/2020.10.24.353581

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.

Cheung, C. H. P.·Alorabi, M.·Hamilton, F.·Takebayashi, Y.·Mounsey, O.·Heesom, K. J.·Williams, P. B.·Williams, M.·Albur, M.·MacGowan, A. P.·Avison, M. B.

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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-{beta}-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.

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Cheung, C. H. P., Alorabi, M., Hamilton, F., Takebayashi, Y., Mounsey, O., Heesom, K. J., Williams, P. B., Williams, M., Albur, M., MacGowan, A. P., Avison, M. B.. 2020-10-25. 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.. https://doi.org/10.1101/2020.10.24.353581

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