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

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.