Morin combined with meropenem is a potent inhibitor of NDM-1 against NDM-1-producing E. coli.

Some β-lactam antibiotics are hydrolyzed by the enzyme New Delhi metallo-β-lactamase 1 (NDM-1), increasing antibiotic resistance and posing a significant threat to public health. Thus, there is an urgent need to develop and use potent inhibitors of NDM-1 and other β-lactamases. This study evaluated the effects of the flavonoid morin (3,5,7,2',4'-pentahydroxyflavone) on the antimicrobial activity of β-lactams and the interaction between morin and NDM-1. New NDM-1 inhibitors were identified by the structure-based virtual screening of natural product libraries. The interaction between morin and NDM-1 was evaluated by molecular docking. The impact of morin on β-lactam activity was assessed in vitro using checkerboard tests, kill-time kinetics, and broth microdilution. The effect of morin on the anti-inflammatory activity of meropenem (MEM) in BALB/c mice infected with NDM-1-producing Escherichia coli was evaluated by ELISA. The impact of morin and MEM on mouse tissue damage was assessed by hematoxylin and eosin staining. The interaction mechanisms between morin and NDM-1 were examined using molecular dynamics simulations. Molecular docking showed that morin inhibited NDM-1. Morin alone did not inhibit the growth of NDM-1-producing E. coli. However, morin combined with β-lactams suppressed bacterial growth and reduced their MIC 4- to 32-fold. Morin combined with MEM decreased tissue damag Morin enhanced antibacterial activity of β-lactams against NDM-1-producing E. coli when combined with MEM. These findings establish the foundation for using morin in developing potent inhibitors for NDM-1 and other β-lactamases to reduce antibiotic resistance.