Novel specific metallo-b-lactamase inhibitor ANT2681 restores meropenem activity to clinically effective levels against NDM-positive enterobacterales

Abstract

The global dissemination of metallo-b-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) is a serious public health concern. Specifically, NDM (New Delhi MBL) has been a major cause of carbapenem therapy failures in recent years, particularly as effective treatments for serine-b-lactamase (SBL)-producing Enterobacterales are now commercially available. Since the NDM gene is carried on promiscuous plasmids encoding multiple additional resistance determinants, a large proportion of NDM-CREs are also resistant to many commonly used antibiotics, resulting in limited and suboptimal treatment options. ANT2681 is a specific, competitive inhibitor of MBLs with potent activity against NDM enzymes, progressing to clinical development in combination with meropenem (MEM). Susceptibility studies have been performed with MEMANT2681 against 1,687 MBL-positive Enterobacterales, including 1,108 NDM-CRE. The addition of ANT2681 at 8mg/ml reduced the MEM MIC50/MIC90 from .32/ >32mg/ml to 0.25/8mg/ml. Moreover, the combination of 8mg/ml of both MEM and ANT2681 inhibited 74.9% of the Verona integron-encoded MBL (VIM)positive and 85.7% of the imipenem hydrolyzing b-lactamase (IMP)-positive Enterobacterales tested. The antibacterial activity of MEM-ANT2681 against NDM-CRE compared very favorably to that of cefiderocol (FDC) and cefepime (FEP)-taniborbactam, which displayed MIC90 values of 8mg/ml and 32mg/ml, respectively, whereas aztreonam-avibactam (ATM-AVI) had a MIC90 of 0.5mg/ml. Particularly striking was the activity of MEM-ANT2681 against NDM-positive Escherichia coli (MIC90 1mg/ml), in contrast to ATM-AVI (MIC90 4mg/ml), FDC (MIC90 .32mg/ml), and FEP-taniborbactam (MIC90 .32mg/ml), which were less effective due to the high incidence of resistant PBP3-insertion mutants. MEMANT2681 offers a potential new therapeutic option to treat serious infections caused by NDM-CRE.