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 beta-lactam antibacterials. The development of effective metallo-beta-lactamase (M beta L) inhibitors to restore the existing antibiotics efficacy is an ideal alternative. Although several types of serine-beta-lactamase inhibitors have been successfully developed and used in clinical settings, M beta L 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 M beta Ls and effectively revived Meropenem efficacy against M beta L-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 M beta Ls.