Novel Specific Metallo- ß-lactamase Inhibitor, ANT2681, Restores Meropenem Activity to Clinically Effective Levels Against NDM-Positive Enterobacterales

Antimicrob Agents Chemother. 2021 Apr 5:AAC.00203-21. doi: 10.1128/AAC.00203-21. Online ahead of print.ABSTRACTThe global dissemination of metallo-ß-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-ß-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 sub-optimal 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. Addition of ANT2681 at 8 μg/ml reduced 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 VIM-positive and 85.7% of the IMP-positive Enterobacterales tested. The antibacterial activity of MEM-ANT2681 against NDM-CRE compared very favourably to that of cefiderocol (FDC) and cefepime (FEP)-taniborbactam, which displayed MIC90 values of 8 μg/ml and 32 μg/ml, respectivel...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Source Type: research