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 β-lactamase enzymes which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and can result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine-β-lactamases (SBLs, e.g. KPC-2 and OXA-48) and metallo-β-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 β-lactam antibiotics with β-lactamase inhibitors are only active 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 MEM against a broad range of MBL-producing CRE, and restore its efficacy against anEscherichia coliNDM-1 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 CREs and address an important and growing unmet medical need.

Everett, M., Sprynski, N., Coelho, A., Castandet, J., Bayet, M., Bougnon, J., et al. (2018). Discovery of a Novel Metallo-β-Lactamase Inhibitor that Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 62(5), 1-11 [10.1128/AAC.00074-18].

Discovery of a Novel Metallo-β-Lactamase Inhibitor that Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae

De Luca, Filomena;Docquier, Jean-Denis;
2018-01-01

Abstract

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 β-lactamase enzymes which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and can result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine-β-lactamases (SBLs, e.g. KPC-2 and OXA-48) and metallo-β-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 β-lactam antibiotics with β-lactamase inhibitors are only active 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 MEM against a broad range of MBL-producing CRE, and restore its efficacy against anEscherichia coliNDM-1 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 CREs and address an important and growing unmet medical need.
Everett, M., Sprynski, N., Coelho, A., Castandet, J., Bayet, M., Bougnon, J., et al. (2018). Discovery of a Novel Metallo-β-Lactamase Inhibitor that Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 62(5), 1-11 [10.1128/AAC.00074-18].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1039814