Gold-Based Agents as Promising Metallo-β-lactamase Inhibitors

Abstract

Antimicrobial resistance (AMR), which confers bacteria resistance to antimicrobial agents, has been spotlighted as one of the top threats to global health. Production of metallo-β-lactamase (MBLs) is one of the resistance mechanisms that confronts β-lactam antibiotics including penicillins and carbapenems.1 We have previously discovered that bismuth- and gold-based2,3 drugs and relevant agents are effective inhibitors to B1 subclass of MBL. In this study, we extended the investigation to B2 subclass of MBL, exemplifying with Sfh-I and CphA. We demonstrate that Au-based agents exhibite excellent antimicrobial activity against both Sfh-I- and CphA-positive bacteria. Auranofin (AUR) had synergistic effect with meropenem (MER), reducing minimum inhibitory concentration (MIC) of MER by 32-folds and 8-folds, respectively on Sfh-I+ and CphA+ bacteria. The bacterial loads under combination therapy of AUR and MER on CphA+ bacteria were found to be enormously diminished after 20 hrs in contrast to individual treatment components. IC50 of 0.55 μM (± 0.01 μM) was found on Sfh-I enzyme in the presence of Au. We therefore conclude that Au-based agents may prohibits hydrolysis of antibiotic also on B2 MBLs and thus can serve as an inhibitor. In vivo study is in progress in this laboratory.