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

Area of Science:

• Microbiology
• Biochemistry
• Pharmacology

Background:

• Bacterial resistance to antibiotics, particularly metallo-β-lactamases (MBLs), is a significant global health concern.
• Metallo-β-lactamases confer resistance to β-lactam antibiotics, including crucial carbapenems.
• Existing therapeutic options are limited, necessitating novel strategies to overcome MBL-mediated resistance.

Purpose of the Study:

• To investigate the potential of α-lipoic acid (LA) and methimazole (MMI) as inhibitors of metallo-β-lactamases (MBLIs).
• To evaluate the synergistic antibacterial effects of LA and MMI in combination with meropenem (MER) against MBL-producing bacteria.

Main Methods:

• Enzyme inhibition assays were performed to assess the inhibitory activity of LA and MMI against specific MBLs (NDM-1, VIM-2, IMP-7).
• Antibacterial synergy assays, including minimum inhibitory concentration (MIC) and fractional inhibitory concentration index (FICI) calculations, were conducted.
• Time-kill kinetic studies were employed to evaluate the restored antibacterial effect of meropenem in combination with LA or MMI.

Main Results:

• LA and MMI exhibited moderate inhibition against NDM-1 but lacked activity against VIM-2 and IMP-7.
• Combinations of LA or MMI with meropenem significantly reduced MER's MIC values against NDM-1-producing E. coli (16-fold and 4-fold, respectively).
• FICI values below 0.5 confirmed synergistic antibacterial effects between LA/MMI and MER against all tested MBL-producing E. coli strains.

Conclusions:

• α-lipoic acid and methimazole demonstrate potential as carbapenem enhancers, effectively restoring meropenem's activity against MBL-producing bacteria.
• These non-antibiotic compounds offer a promising starting point for the development of novel metallo-β-lactamase inhibitors.
• The findings highlight a potential strategy to combat the growing threat of antibiotic resistance mediated by MBLs.