Identification of Cisplatin and Palladium(II) Complexes as Potent Metallo-β-lactamase Inhibitors for Targeting Carbapenem-Resistant Enterobacteriaceae

The emergence and prevalence of carbapenem-resistant bacterial infection have seriously threatened the clinical use of almost all β-lactam antibacterials. The development of effective metallo-β-lactamase (MβL) inhibitors to restore the existing antibiotics efficacy is an ideal alternative. Although several types of serine-β-lactamase inhibitors have been successfully developed and used in clinical settings, MβL inhibitors are not clinically available to date. Herein, we identified that cisplatin and Pd(II) complexes are potent broad-spectrum inhibitors of the B1 and B2 subclasses of MβLs and effectively revived Meropenem efficacy against MβL-expressing bacteria in vitro. Enzyme kinetics, thermodynamics, inductively coupled plasma atomic emission spectrometry (ICP-AES), matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS), and site-directed mutation assays revealed that these metal complexes irreversibly inhibited NDM-1 through a novel inhibition mode involving binding to Cys208 and displacing one Zn(II) ion of the enzyme with one Pt(II) containing two NH₃'s or one Pd(II) ion. Importantly, the combination therapy of Meropenem and metal complexes significantly suppressed the development of higher-level resistance in bacteria producing NDM-1, also effectively reduced the bacterial burden in liver and spleen of mice infected by carbapenem-resistant Enterobacteriaceae producing NDM-1. These findings will offer potential lead compounds for the further development of clinically useful inhibitors targeting MβLs.