Gallium-Based Agents as an Inhibitor of Metallo-β-Lactamase

Abstract

Being the top ten threats to global health in 2019 as enumerated by the World Health Organization (WHO), antimicrobial resistance (AMR) empowers bacteria the ability in confronting existing antimicrobial agents. Metallo-β-lactamase (MBLs), exemplifying with New Delhi metallo-β-lactamase 1 (NDM-1), which is a subclass B1 MBL and able to hydrolyze almost all β-lactam antibiotics, including the last resort carbapenems. Combination therapy is regarded as one of the promising approaches in combating AMR. We previously found that metallo-agents are potential MBL inhibitors [1]. Despite the fact that gallium-based agents are well-known for their therapeutic activity in cancers, infections and inflammatory conditions [2], previous studies demonstrated that clinically approved gallium compounds exhibited antibacterial activity against several human pathogens, including ESKAPE species [3,4], aligning with our findings. Here, we found that gallium-based agents exhibited good antimicrobial activity against MBL-positive bacteria. We show that gallium complexes had synergistic effect with meropenem (MER), could reduce the minimum inhibitory concentration (MIC) of MER by 16-folds, with a fractional inhibitory concentration (FIC) index of 0.375. Co-treatment of gallium complexes could reduce bacterial density by over 10,000-folds in comparison with any single component after 8 hrs, indicative of remarkably enhanced bactericidal activity of MER, while gallium itself showed no inhibition to bacterial growth. Enzyme assay showed that enzymatic activity was almost completely retarded in the presence of gallium, with a half-maximum inhibitory concentration (IC50) of 262.9 μM (±44.5 μM). We therefore conclude that gallium-based agents may serve as promising antimicrobial candidates to combat AMR caused by MBL producing bacteria. We thank the Research Grants Council of Hong Kong (R7070-18) and the University of Hong Kong for their support of this work.