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

doi:10.1038/s41598-020-57844-8

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 journal › Article › peer-review

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 language	English
Article number	928
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-57844-8
Publication status	Published - 27 Jan 2020

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Effect of Amoxicillin in combination with Imipenem-Relebactam
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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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AU - Harrison, James

AU - Rathbone, Dan

AU - Desai, Maya

AU - Lambert, Peter

AU - Cox, Jonathan A.G.

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N2 - 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.

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

Abstract

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Author Correction: Effect of Amoxicillin in combination with Imipenem-Relebactam against Mycobacterium abscessus (Scientific Reports, (2020), 10, 1, (928), 10.1038/s41598-020-57844-8)

Investigating Mycobacterium abscessus to inform treatment and drug discovery

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

Abstract

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Research output

Author Correction: Effect of Amoxicillin in combination with Imipenem-Relebactam against Mycobacterium abscessus (Scientific Reports, (2020), 10, 1, (928), 10.1038/s41598-020-57844-8)

Student theses

Investigating Mycobacterium abscessus to inform treatment and drug discovery

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