Effect of Amoxicillin in combination with Imipenem-Relebactam against Mycobacterium abscessus

Rose C. Lopeman, James Harrison, Dan Rathbone, Maya Desai, Peter Lambert, Jonathan A.G. Cox*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Infections caused by Mycobacterium abscessus are increasing in prevalence in cystic fibrosis patients. This opportunistic pathogen′s intrinsic resistance to most antibiotics has perpetuated an urgent demand for new, more effective therapeutic interventions. Here we report a prospective advance in the treatment of M. abscessus infection; increasing the susceptibility of the organism to amoxicillin, by repurposing the β-lactamase inhibitor, relebactam, in combination with the front line M. abscessus drug imipenem. We establish by multiple in vitro methods that this combination works synergistically to inhibit M. abscessus. We also show the direct competitive inhibition of the M. abscessus β-lactamase, BlaMab, using a novel assay, which is validated kinetically using the nitrocefin reporter assay and in silico binding studies. Furthermore, we reverse the susceptibility by overexpressing BlaMab in M. abscessus, demonstrating relebactam-BlaMab target engagement. Finally, we highlight the in vitro efficacy of this combination against a panel of M. abscessus clinical isolates, revealing the therapeutic potential of the amoxicillin-imipenem-relebactam combination.
Original languageEnglish
Article number928
JournalScientific Reports
Volume10
Issue number1
DOIs
Publication statusPublished - 27 Jan 2020

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Imipenem
Amoxicillin
Mycobacterium
Mycobacterium Infections
Cystic Fibrosis
Computer Simulation
Therapeutics
Anti-Bacterial Agents
Infection
Pharmaceutical Preparations
MK-7655
In Vitro Techniques

Cite this

@article{ae9990c5ff304d8187f877929b620e00,
title = "Effect of Amoxicillin in combination with Imipenem-Relebactam against Mycobacterium abscessus",
abstract = "Infections caused by Mycobacterium abscessus are increasing in prevalence in cystic fibrosis patients. This opportunistic pathogen′s intrinsic resistance to most antibiotics has perpetuated an urgent demand for new, more effective therapeutic interventions. Here we report a prospective advance in the treatment of M. abscessus infection; increasing the susceptibility of the organism to amoxicillin, by repurposing the β-lactamase inhibitor, relebactam, in combination with the front line M. abscessus drug imipenem. We establish by multiple in vitro methods that this combination works synergistically to inhibit M. abscessus. We also show the direct competitive inhibition of the M. abscessus β-lactamase, BlaMab, using a novel assay, which is validated kinetically using the nitrocefin reporter assay and in silico binding studies. Furthermore, we reverse the susceptibility by overexpressing BlaMab in M. abscessus, demonstrating relebactam-BlaMab target engagement. Finally, we highlight the in vitro efficacy of this combination against a panel of M. abscessus clinical isolates, revealing the therapeutic potential of the amoxicillin-imipenem-relebactam combination.",
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Effect of Amoxicillin in combination with Imipenem-Relebactam against Mycobacterium abscessus. / Lopeman, Rose C.; Harrison, James; Rathbone, Dan; Desai, Maya; Lambert, Peter; Cox, Jonathan A.G. .

In: Scientific Reports, Vol. 10, No. 1, 928, 27.01.2020.

Research output: Contribution to journalArticle

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AU - Harrison, James

AU - Rathbone, Dan

AU - Desai, Maya

AU - Lambert, Peter

AU - Cox, Jonathan A.G.

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AB - Infections caused by Mycobacterium abscessus are increasing in prevalence in cystic fibrosis patients. This opportunistic pathogen′s intrinsic resistance to most antibiotics has perpetuated an urgent demand for new, more effective therapeutic interventions. Here we report a prospective advance in the treatment of M. abscessus infection; increasing the susceptibility of the organism to amoxicillin, by repurposing the β-lactamase inhibitor, relebactam, in combination with the front line M. abscessus drug imipenem. We establish by multiple in vitro methods that this combination works synergistically to inhibit M. abscessus. We also show the direct competitive inhibition of the M. abscessus β-lactamase, BlaMab, using a novel assay, which is validated kinetically using the nitrocefin reporter assay and in silico binding studies. Furthermore, we reverse the susceptibility by overexpressing BlaMab in M. abscessus, demonstrating relebactam-BlaMab target engagement. Finally, we highlight the in vitro efficacy of this combination against a panel of M. abscessus clinical isolates, revealing the therapeutic potential of the amoxicillin-imipenem-relebactam combination.

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