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

Autor: Zalacain M; Antabio SAS, Labège, France magdalena.zalacain@antabio.com., Lozano C; Antabio SAS, Labège, France., Llanos A; Antabio SAS, Labège, France., Sprynski N; Antabio SAS, Labège, France., Valmont T; IHMA Europe Sàrl, Monthey, Switzerland., De Piano C; IHMA Europe Sàrl, Monthey, Switzerland., Davies D; Antabio SAS, Labège, France., Leiris S; Antabio SAS, Labège, France., Sable C; Antabio SAS, Labège, France., Ledoux A; Antabio SAS, Labège, France., Morrissey I; IHMA Europe Sàrl, Monthey, Switzerland., Lemonnier M; Antabio SAS, Labège, France., Everett M; Antabio SAS, Labège, France.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2021 May 18; Vol. 65 (6). Date of Electronic Publication: 2021 May 18 (Print Publication: 2021).
DOI: 10.1128/AAC.00203-21
Abstrakt: 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 MIC 50 /MIC 90 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 MIC 90 values of 8 μg/ml and 32 μg/ml, respectively, whereas aztreonam-avibactam (ATM-AVI) had a MIC 90 of 0.5 μg/ml. Particularly striking was the activity of MEM-ANT2681 against NDM-positive Escherichia coli (MIC 90 1 μg/ml), in contrast to ATM-AVI (MIC 90 4 μg/ml), FDC (MIC 90 >32 μg/ml), and FEP-taniborbactam (MIC 90 >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.
(Copyright © 2021 Zalacain et al.)
Databáze: MEDLINE
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