Theaflavin-3,3´-digallate increases the antibacterial activity of β-lactam antibiotics by inhibiting metallo-β-lactamase activity

Journal of Cellular and Molecular Medicine
Zihao TengJianfeng Wang

Abstract

Metallo-β-lactamases (MBLs) are some of the best known β-lactamases produced by common Gram-positive and Gram-negative pathogens and are crucial factors in the rise of bacterial resistance against β-lactam antibiotics. Although many types of β-lactamase inhibitors have been successfully developed and used in clinical settings, no MBL inhibitors have been identified to date. Nitrocefin, checkerboard and time-kill assays were used to examine the enzyme behaviour in vitro. Molecular docking calculation, molecular dynamics simulation, calculation of the binding free energy and ligand-residue interaction decomposition were used for mechanistic research. The behaviour of the enzymes in vivo was investigated by a mouse infection experiment. We showed that theaflavin-3,3´-digallate (TFDG), a natural compound lacking antibacterial activities, can inhibit the hydrolysis of MBLs. In the checkerboard and time-kill assays, we observed a synergistic effect of TFDG with β-lactam antibiotics against methicillin-resistant Staphylococcus aureus BAA1717. Molecular dynamics simulations were used to identify the mechanism of the inhibition of MBLs by TFDG, and we observed that the hydrolysis activity of the MBLs was restricted by the binding of TFD...Continue Reading

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Citations

Oct 1, 2020·Dalton Transactions : an International Journal of Inorganic Chemistry·Cheng Chen, Kewu Yang
Mar 28, 2020·International Journal of Environmental Research and Public Health·Yanling WangJianfeng Wang
Dec 19, 2020·Microbiological Research·Thankaraj Rajam Jabila MarySamuel Gnana Prakash Vincent
Dec 20, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Zhongyuan LiYonglian Guo

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Methods Mentioned

BETA
light microscopy

Software Mentioned

antechamber
Amber
Gromacs
APBS
AutoDock
PyMOL
Gaussian 09
MODELLER
AutoGrid

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