Cobalt(III) Schiff Base Complexes as Irreversible Inhibitors of the Metallo-β-Lactamase NDM-1

Antibiotic resistance is a critical global health concern. Roughly 2.8 million Americans are infected with antibiotic-resistant bacteria each year, leading to over 35,000 deaths. Of particular concern are Enterobacterales that express metallo-β-lactamases (MBLs), as these bacteria can exhibit resistance to most β-lactam drugs, including carbapenems, and are often contracted in the hospital. As of June 2025, no FDA approved MBL inhibitors yet exist, leaving a critical gap in therapeutic options for MBL-expressing Enterobacterales infections. The active sites of MBLs differ from that of serine β-lactamases in that many contain two histidine-bound Zn(II) ions that catalyze β-lactam hydrolysis via a nucleophilic hydroxide. Previous work in the Meade lab has shown that Cobalt(III) Schiff base complexes (Co(III)-sb) displace histidine-bound Zn(II) ions from structural sites, resulting in inhibition of protein function, making Co(III)-sb complexes a prime candidate for MBL inhibition. In this work, Metallo-β-Lactamase 1 (NDM-1) susceptibility to inhibition by Co(III)-sb was spectroscopically and biochemically validated. Inhibition was confirmed to be irreversible and axial ligand dependent. The potency and kinetics of irreversible inhibition were probed with a library of cobalt complexes. Axial ligand lability was correlated positively with inhibition based on trends in 59Co spectra of each complex. Tested complexes exhibited little-to-no mammalian cell toxicity. To build upon these results, further chemical modification of the complexes will be required to enable them to cross the Gram(-) envelope.