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

Abstract

Infections caused by carbapenem-resistant (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 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 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 NDM-1-producing 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.

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

“…Combinations of β-lactams and β-lactam enhancers such as zidebactam (13) and nacubactam (14) have also shown promising activities. Moreover, several MBL inhibitors, including aspergillomarasmine A (15), dipicolinic acid derivatives (16), ANT431 (17), bisthiazolodines (18) and bismuth antimicrobials (19) have been reported. Recently, VNRX-5133 (taniborbactam), a dual SBL and MBL inhibitor have shown potent activity in combination with cefepime against MBL-producers (20).…”

Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance

“…Indeed, many research groups have developed MBL inhibitors and confirmed their activity against purified MBL enzymes in vitro; however, most inhibitors showed extremely low activity toward live MBL-producing bacteria, suggesting that their permeativity of the bacterial outer membrane is low (7). Thus, only a few MBL inhibitors, such as ME1071, developed by Meiji Seika Pharma (8), and cyclic boronates (9,10), including VNRX-5133 (taniborbactam), developed by Venatorx (11)(12)(13), and ANT431, developed by Antabio SAS (14), are reportedly active against MBL-producing clinical isolates. Nonetheless, none of these compounds have been approved for clinical use.…”

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

“…Representative inhibitors of NDM-1 [28][29][30][31][32][33][34][35][36]. ChemMedChem 2019, 14,1271 -1282 www.chemmedchem.org 2019 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 3, 5, 6,a nd 8 are summarized in Scheme 2.…”