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


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.

Publication DOI: https://doi.org/10.1038/s41598-020-57844-8
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences > Chronic and Communicable Conditions
Uncontrolled Keywords: General
Publication ISSN: 2045-2322
Full Text Link:
Related URLs: https://www.nat ... 598-020-57844-8 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2020-01-27
Accepted Date: 2020-01-06
Authors: Lopeman, Rose C.
Harrison, James
Rathbone, Dan (ORCID Profile 0000-0003-4732-4662)
Desai, Maya
Lambert, Peter (ORCID Profile 0000-0002-8243-2741)
Cox, Jonathan A.G. (ORCID Profile 0000-0001-5208-4056)



Version: Published Version

License: Creative Commons Attribution

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