Development and in vitro evaluation of 1,4,7-triazacyclononane-coupled β-lactams against metallo-β-lactamase producing bacteria

Abstract

Antimicrobial resistance (AMR) is a critical global issue, particularly against β-lactam antibiotics, which comprise over 60% of prescriptions. Metallo-β-lactamases (MBLs) are especially concerning as they inactivate nearly all β-lactams, except monobactams. Unlike serine-β-lactamases (SBLs), for which inhibitors exist, there are no clinically approved MBL inhibitors; only taniborbactam is in pre-registration. This study introduces eight new MBL inhibitors (13a–f, 14a-b), designed using a 1,4,7-triazacyclononane (NO3PY) chelator linked to a β-lactam. These inhibitors restored the efficacy of meropenem, reducing its minimum inhibitory concentration (MIC) against MBL-expressing pathogens to <2 mg L⁻¹. Time-kill assays confirmed bactericidal activity, with this series being non-toxic and highly specific, these compounds hold promising potential as MBL inhibitors.