Chelate-conjugated β-lactams resensitize metallo-β-lactamase IMP-1-producing gram-negative bacteria against carbapenem antibiotics.

Metallo-β-lactamases (MBLs) such as IMP-1 are zinc-dependent enzymes that degrade a wide range of β-lactam antibiotics, including carbapenems. Although many efforts have been made to develop MBL inhibitors, there are no approved inhibitors to date. Polycarboxylated amoxicillin, such as diethylenetriaminepentaacetic acid (DTPA)-conjugated amoxicillin, has been developed as a potent antipseudomonal antibiotic. Interestingly, it effectively killed IMPORTANCE: The global rise of antibiotic-resistant bacteria has become a serious threat to public health. Among them, gram-negative bacteria harboring metallo-β-lactamase (MBL) genes, which inactivate carbapenems-the last-resort antibiotics-pose a particular challenge due to the lack of effective therapeutic options. In this study, we developed β-lactam-based compounds incorporating a metal-chelating moiety designed to inhibit MBL. These compounds demonstrated potent inhibitory activity against MBL. Moreover, when combined with carbapenems, they significantly restored antibacterial efficacy in MBL-producing strains. Despite their structural simplicity, the compounds offer substantial flexibility in chemical modification, allowing for tailored optimization against different resistant pathogens. These findings suggest that such inhibitors could serve as promising candidates for novel combination therapies targeting MBL-mediated resistance, contributing to the development of next-generation antimicrobial strategies.