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

Abstract Antibiotic resistance is a critical public health concern, with approximately 2.8 million Americans infected with antibiotic-resistant bacteria annually and over 35,000 deaths in the United States alone. Of particular concern are Enterobacterales that express metallo-β-lactamases (MBLs), bacteria that cause nosocomial infections and exhibit resistance to most β-lactam drugs. The zinc-containing active sites of MBLs differ from those of serine β-lactamases, making current clinical inhibitors ineffective. No FDA-approved MBL inhibitors exist, leaving a critical gap in therapeutics for MBL-expressing Enterobacterales infections. Herein, we biochemically and spectroscopically demonstrate irreversible inhibition of the metallo-β-lactamase NDM-1 by a subset of cobalt(III) Schiff base complexes (Co(III)-sb). Crystallography and 59Co NMR experiments show that inactivation efficiency is dependent on axial and equatorial ligand identity. While Co(III)-sb exhibits NDM-1 inhibition, chemical modification is required to enable complexes to cross the Gram-negative envelope. These findings establish Co(III)-sb complexes as a novel scaffold for the development of MBL inhibitors.