Probing metallo-β-lactamases with molecular fragments identified by consensus docking

Area of Science:

• Microbiology and Infectious Diseases
• Drug Discovery and Development
• Computational Chemistry

Background:

• Metallo-β-lactamases (MBLs) confer bacterial resistance to crucial β-lactam antibiotics.
• The emergence of MBL-producing bacteria poses a significant threat to public health, limiting treatment options.
• Developing novel MBL inhibitors is essential to combat antimicrobial resistance.

Purpose of the Study:

• To identify novel low molecular weight fragments that inhibit clinically relevant MBLs (NDM-1, VIM-1, IMP-7) using an in silico approach.
• To establish a foundation for fragment-based drug design targeting MBLs.
• To discover starting points for developing new therapeutic agents against MBL-mediated resistance.

Main Methods:

• In silico screening using consensus docking to identify potential fragment binders from a commercial library.
• In vitro validation using a fluorescence-based activity assay to assess inhibitory potential.
• Biophysical characterization via saturation transfer difference (STD)-NMR and (1)H-(15)N chemical shift perturbation NMR to confirm binding and determine dissociation constants.

Main Results:

• Identification of several low molecular weight compounds with potential to inhibit NDM-1, VIM-1, and IMP-7.
• Experimental validation confirmed the inhibitory activity and binding of promising fragments.
• Characterization of a high-quality fragment demonstrating reversible binding and a measurable dissociation constant.

Conclusions:

• The in silico fragment-based approach successfully identified novel starting points for MBL inhibitor development.
• These validated fragments represent promising leads for optimizing into potent inhibitors to combat MBL-mediated antibiotic resistance.
• This study provides a valuable foundation for the rational design of new drugs to overcome a critical challenge in infectious disease treatment.