Discovery of a novel metallo-beta-lactamase inhibitor that potentiates meropenem activity against carbapenem-resistant enterobacteriaceae

Everett, M.; Sprynski, N.; Coelho, A.; Castandet, J.; Bayet, M.; Bougnon, J.; Lozano, C.; Davies, D. T.; Leiris, S.; Zalacain, M.; Morrissey, I.; Magnet, S.; Holden, K.; Warn, P.; De Luca, F.; Docquier, Jean-Denis; Lemonniera, M.

doi:10.1128/AAC.00074-18

Article (Scientific journals)

Discovery of a novel metallo-beta-lactamase inhibitor that potentiates meropenem activity against carbapenem-resistant enterobacteriaceae

Everett, M.; Sprynski, N.; Coelho, A. et al.

2018 • In Antimicrobial Agents and Chemotherapy, 62 (5)

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/252547

DOI
10.1128/AAC.00074-18

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29530861

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Keywords :

Carbapenem; Inhibitor; Metallo--lactamase; NDM-1; Resistance; Article; Citrobacter freundii; Enterobacter cloacae; Escherichia coli; Escherichia coli infection; Klebsiella pneumoniae; Morganella morganii; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Meropenem; Microbial Sensitivity Tests

Abstract :

[en] Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of beta-lactamase enzymes, which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine beta-lactamases (SBLs; e.g., KPC-2 and OXA-48) and metallo-beta-lactamases (MBLs), such as NDM-1. MBL-producing strains are endemic within the community in many Asian countries, have successfully spread worldwide, and account for many significant CRE outbreaks. Recently approved combinations of beta-lactam antibiotics with beta-lactamase inhibitors are active only against SBL-producing pathogens. Therefore, new drugs that specifically target MBLs and which restore carbapenem efficacy against MBL-producing CRE pathogens are urgently needed. Here we report the discovery of a novel MBL inhibitor, ANT431, that can potentiate the activity of meropenem (MEM) against a broad range of MBL-producing CRE and restore its efficacy against an Escherichia coli NDM-1producing strain in a murine thigh infection model. This is a strong starting point for a chemistry lead optimization program that could deliver a first-in-class MBL inhibitor-carbapenem combination. This would complement the existing weaponry against CRE and address an important and growing unmet medical need. © 2018 American Society for Microbiology. All Rights Reserved.

Disciplines :

Microbiology

Author, co-author :

Everett, M.; Antabio SAS, Labège, France

Sprynski, N.; Antabio SAS, Labège, France

Coelho, A.; Antabio SAS, Labège, France

Castandet, J.; Antabio SAS, Labège, France

Bayet, M.; Antabio SAS, Labège, France

Bougnon, J.; Antabio SAS, Labège, France

Lozano, C.; Antabio SAS, Labège, France

Davies, D. T.; Antabio SAS, Labège, France

Leiris, S.; Antabio SAS, Labège, France

Zalacain, M.; Antabio SAS, Labège, France, Zala Drug Discovery Consulting LLC, West Chester, PA, United States

More authors (7 more)

Language :

English

Title :

Discovery of a novel metallo-beta-lactamase inhibitor that potentiates meropenem activity against carbapenem-resistant enterobacteriaceae

Publication date :

2018

Journal title :

Antimicrobial Agents and Chemotherapy

ISSN :

0066-4804

eISSN :

1098-6596

Publisher :

American Society for Microbiology

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

Wellcome Trust

Available on ORBi :

since 13 November 2020

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