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

doi:10.1128/AAC.02412-20

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

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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 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 language	English
Article number	e02412-20
Journal	Antimicrobial Agents and Chemotherapy
Volume	65
Issue number	8
Early online date	10 May 2021
DOIs	https://doi.org/10.1128/AAC.02412-20
Publication status	Published - 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).

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

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This research was funded in whole, or in part, by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This is the author accepted manuscript (AAM). The final published version (version of record) is available online via American Society for Microbiology Journals at https://doi.org/10.1128/AAC.02412-20 . Please refer to any applicable terms of use of the publisher.
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Phoebe Cheung, C. H., Alorabi, M., Hamilton, F., Takebayashi, Y., Mounsey, O., Heesom, K. J., Williams, P. B., Williams, O. M., Albur, M., MacGowan, A. P., & Avison, M. B. (2021). 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. Antimicrobial Agents and Chemotherapy, 65(8), Article e02412-20. https://doi.org/10.1128/AAC.02412-20

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title = "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",

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.",

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

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 {\textcopyright} 2021 American Society for Microbiology. All Rights Reserved.",

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doi = "10.1128/AAC.02412-20",

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Phoebe Cheung, CH, Alorabi, M, Hamilton, F , Takebayashi, Y , Mounsey, O , Heesom, KJ, Williams, PB, Williams, OM, Albur, M, MacGowan, AP & Avison, MB 2021, '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', Antimicrobial Agents and Chemotherapy, vol. 65, no. 8, e02412-20. https://doi.org/10.1128/AAC.02412-20

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. / Phoebe Cheung, Ching Hei; Alorabi, Mohammed; Hamilton, Fergus et al.
In: Antimicrobial Agents and Chemotherapy, Vol. 65, No. 8, e02412-20, 16.07.2021.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - 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

AU - Phoebe Cheung, Ching Hei

AU - Alorabi, Mohammed

AU - Hamilton, Fergus

AU - Takebayashi, Yuiko

AU - Mounsey, Oliver

AU - Heesom, Kate J

AU - Williams, Philip B

AU - Williams, O Martin

AU - Albur, Mahableshwar

AU - MacGowan, Alasdair P

AU - Avison, Matthew B

N1 - 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.

PY - 2021/7/16

Y1 - 2021/7/16

N2 - 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.

AB - 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.

U2 - 10.1128/AAC.02412-20

DO - 10.1128/AAC.02412-20

M3 - Article (Academic Journal)

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Phoebe Cheung CH, Alorabi M, Hamilton F , Takebayashi Y , Mounsey O , Heesom KJ et al. 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. Antimicrobial Agents and Chemotherapy. 2021 Jul 16;65(8):e02412-20. Epub 2021 May 10. doi: 10.1128/AAC.02412-20

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

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