Novel Specific Metallo-β-Lactamase Inhibitor ANT2681 Restores Meropenem Activity to Clinically Effective Levels against NDM-Positive <i>Enterobacterales</i>

Abstract

The global dissemination of metallo-β-lactamase (MBL)-producing carbapenem-resistant <i>Enterobacterales</i> (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-β-lactamase (SBL)-producing <i>Enterobacterales</i> 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 MEM-ANT2681 against 1,687 MBL-positive <i>Enterobacterales</i>, including 1,108 NDM-CRE. The addition of ANT2681 at 8 μg/ml reduced the MEM MIC₅₀/MIC₉₀ from >32/>32 μg/ml to 0.25/8 μg/ml. Moreover, the combination of 8 μg/ml of both MEM and ANT2681 inhibited 74.9% of the Verona integron-encoded MBL (VIM)-positive and 85.7% of the imipenem hydrolyzing β-lactamase (IMP)-positive <i>Enterobacterales</i> 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 8 μg/ml and 32 μg/ml, respectively, whereas aztreonam-avibactam (ATM-AVI) had a MIC₉₀ of 0.5 μg/ml. Particularly striking was the activity of MEM-ANT2681 against NDM-positive <i>Escherichia coli</i> (MIC₉₀ 1 μg/ml), in contrast to ATM-AVI (MIC₉₀ 4 μg/ml), FDC (MIC₉₀ >32 μg/ml), and FEP-taniborbactam (MIC₉₀ >32 μg/ml), which were less effective due to the high incidence of resistant PBP3-insertion mutants. MEM-ANT2681 offers a potential new therapeutic option to treat serious infections caused by NDM-CRE.