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

Abstract

The 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, respectively, whereas aztreonam-avibactam (ATM-AVI) had an MIC90 of 0.5 μg/ml. Particularly striking was the activity of MEM-ANT2681 against NDM-positive E. 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.

Cefiderocol for the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Systematic Review of Currently Available Evidence

“…Thirty-eight studies reporting on the in vitro activity of cefiderocol against Gram-negative bacteria were included ( Ito et al, 2015 ; Ito et al, 2016 ; Kohira et al, 2015 ; Falagas et al, 2017 ; Dobias et al, 2017 ; Hackel et al, 2017 ; Kanazawa et al, 2017 ; Yamano et al, 2017 ; Hackel et al, 2018 ; Ito et al, 2018a ; Jacobs et al, 2018 ; Karlowsky et al, 2019 ; Kazmierczak et al, 2019 ; Hsueh et al, 2019 ; Iregui et al, 2019 ; Albano et al, 2020 ; Biagi et al, 2020 ; Delgado-Valverde et al, 2020 ; Golden et al, 2020 ; Johnston et al, 2020 ; Kresken et al, 2020 ; Longshaw et al, 2020 ; Morris et al, 2020 ; Mushtaq et al, 2020 ; Rolston et al, 2020 ; Trebosc et al, 2020 ; Abdul-Mutakabbir et al, 2021 ; Bhagwat et al, 2021 ; Bianco et al, 2021 ; Burnard et al, 2021 ; Cercenado et al, 2021 ; Gant et al, 2021 ; Candel et al, 2022 ; Johnston et al, 2021 ; Lee et al, 2021 ; Liu et al, 2021 ; Stracquadanio et al, 2021 ; Zalacain et al, 2021 ). A total of 53,416 isolates, including 34,805 Enterobacterales , 8297 P. aeruginosa , 7249 Acinetobacter spp , 2508 Stenotrophomonas maltophilia and 549 Burkholderia spp , mainly collected from North America, Europe and East Asia excluding Chinese mainland, were tested for cefiderocol susceptibility.…”

β-Lactam Antibiotics and β-Lactamase Enzymes Inhibitors, Part 2: Our Limited Resources

“…In current preclinical studies, ANT-2681 was associated with meropenem. Particularly, the pharmacokinetics/pharmacodynamics of meropenem/ANT-2681 (MEM/ANT-2681) were studied in a murine neutropenic thigh model for the treatment of infections caused by NDM-producing Enterobacteriaceae [134]. Dose-ranging studies were performed with both meropenem and ANT2681.…”

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

“…However, effectiveness on NDM-producing Enterobacterales was suboptimal [ 63 ]. Accordingly, Zalacain et al, when testing the new MBL inhibitor ANT2681 on NDM-producers against comparator agents, found higher effectiveness of a aztreonam/avibactam combination compared to CFDC, especially on E. coli NDM producer [ 64 ].…”