Ruthenium complexes as prospective inhibitors of metallo-β-lactamases to reverse carbapenem resistance

Abstract

The widespread prevalence of metallo-β-lactamase (MβL)-mediated pathogens has seriously caused a loss of efficacy of carbapenem antibacterials, the last resort for the treatment of severe infectious diseases. The development of effective MβL inhibitors is an ideal alternative to restore the efficacy of carbapenems. Here we report that Ru complexes can irreversibly inhibit clinically relevant B1 subclass MβLs (NDM-1, IMP-1 and VIM-2) and potentiate meropenem efficacy against MβL-expressing bacteria in vitro and in a mice infection model. The Cys208 residue at the Zn(II)-binding site and Met67 residue at the β-hairpin loop of an enzyme active pocket are critical for Ru complexes to inhibit NDM-1, which was verified by enzyme kinetics, thermodynamics, NDM-1-C208A mutation and MALDI-TOF-MS analysis. This study will undoubtedly aid efforts to develop metal-based MβL inhibitors in combination with carbapenems to deal with the clinical crisis of carbapenem-resistant E. coli harboring MβLs.