1. Academic Validation
  2. Novel Specific Metallo-β-Lactamase Inhibitor ANT2681 Restores Meropenem Activity to Clinically Effective Levels against NDM-Positive Enterobacterales

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

  • Antimicrob Agents Chemother. 2021 May 18;65(6):e00203-21. doi: 10.1128/AAC.00203-21.
Magdalena Zalacain 1 Clarisse Lozano 2 Agustina Llanos 2 Nicolas Sprynski 2 Thomas Valmont 3 Cyntia De Piano 3 David Davies 2 Simon Leiris 2 Carole Sable 2 Adeline Ledoux 2 Ian Morrissey 3 Marc Lemonnier 2 Martin Everett 2
Affiliations

Affiliations

  • 1 Antabio SAS, Labège, France [email protected].
  • 2 Antabio SAS, Labège, France.
  • 3 IHMA Europe Sàrl, Monthey, Switzerland.
Abstract

The global dissemination of metallo-β-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-β-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 MEM-ANT2681 against 1,687 MBL-positive Enterobacterales, 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 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 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 Escherichia coli (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.

Keywords

ANT2681; NDM; carbapenem-resistant Enterobacterales.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16980
    Antibacterial Agent