Development of Inhibitory Compounds for Metallo-beta-lactamase through Computational Design and Crystallographic...

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Computational Chemistry

Background:

• Metallo-β-lactamases (MBLs) are key contributors to bacterial multidrug resistance by inactivating β-lactam antibiotics.
• MBLs utilize two zinc ions in their active site for catalytic deactivation of antibiotics.

Purpose of the Study:

• To design and synthesize potent inhibitors of metallo-β-lactamases (MBLs).
• To investigate the structure-activity relationship of novel MBL inhibitors based on a quinolinone scaffold.
• To elucidate the binding mechanism of inhibitors to MBLs using X-ray crystallography.

Main Methods:

• Hit compound optimization using computational design and molecular mechanics.
• Organic synthesis of novel quinolinone derivatives.
• In vitro inhibitory activity assays against IMP-1 and NDM-1.
• X-ray crystal structure analysis to determine inhibitor-MBL binding modes.

Main Results:

• A novel quinolinone derivative with a tertiary amine linker demonstrated potent inhibition of MBLs.
• The most active compound exhibited a 50% inhibitory concentration (IC50) of 4.8 μM against IMP-1 and NDM-1.
• X-ray crystallography revealed that the inhibitor's hydrolyzed δ-lactam ring coordinates with zinc ions in the MBL active site.

Conclusions:

• The developed quinolinone-based compounds are promising candidates for combating MBL-mediated antibiotic resistance.
• Structural insights into inhibitor binding provide a foundation for further optimization of MBL inhibitors.
• This study offers a rational design strategy for developing new agents against multidrug-resistant bacteria.