Methimazole and α-lipoic acid as metallo-β-lactamases inhibitors.

Abstract

The emergence of bacterial resistance poses a serious threat to public health. One of the most important resistance mechanisms against β-lactam antibiotics is the production of metallo-β-lactamases (MBLs). In this study, α-lipoic acid (LA) and methimazole (MMI), which have been used in clinical practice as non-antibacterial drugs and as a supplement, were chosen to explore their potential to be metallo-β-lactamases inhibitors (MBLIs). Enzyme inhibition assays showed that LA and MMI had moderate inhibitory activity against NDM-1 but no activity against VIM-2 and IMP-7. Antibacterial assays to determine synergy, demonstrated that the combination of LA or MMI with meropenem (MER) reduced the MIC value of MER against NDM-1 producing E. coli 16 times and 4 times, respectively, lower than that of MER alone. The fractional inhibitory concentration index (FICI) values were calculated to be less than 0.5, indicating that both LA and MMI had synergistic antibacterial effects with MER against all three MBLs expressing E. coli strains. The time-kill studies also suggested that LA and MMI were effective in restoring the antibacterial effect of MER. These findings revealed that LA and MMI are potential carbapenem enhancers, and provide a starting point for the development of potent MBLIs.