Polyphenols as Potential β-Lactamase Inhibitors: An Integrated Computational and Experimental Study

Area of Science:

• Biochemistry
• Pharmacology
• Microbiology

Background:

• β-lactamase production is a primary driver of carbapenem resistance in bacteria.
• Developing effective carbapenemase inhibitors is crucial to combatting antimicrobial resistance.

Purpose of the Study:

• To identify natural polyphenols that can inhibit carbapenemase activity.
• To evaluate the binding affinity, stability, and safety of selected polyphenols against key carbapenemases.
• To assess the antibacterial and synergistic effects of these polyphenols in combination with antibiotics.

Main Methods:

• In silico analysis including molecular docking, molecular dynamics, and ADMET prediction.
• In vitro antibacterial assays and checkerboard analyses against *Klebsiella pneumoniae*, *Escherichia coli*, and *Pseudomonas aeruginosa*.
• Assessment of β-lactam hydrolytic activity inhibition.

Main Results:

• Quercetin, kaempferol, and caffeic acid exhibited strong binding affinity and stability against KPC-2, NDM-1, and OXA-48 carbapenemases.
• Quercetin and kaempferol displayed the highest binding affinities (-8.0 kcal/mol) with stable interactions.
• In vitro studies confirmed antibacterial activity, synergistic effects with cefotaxime, and significant inhibition of β-lactam hydrolysis by quercetin.

Conclusions:

• The studied polyphenols, particularly quercetin and kaempferol, show significant potential as natural β-lactamase inhibitors.
• These compounds possess favorable pharmacokinetic profiles and low toxicity.
• Further in vivo and enzyme kinetic studies are warranted to explore their therapeutic applications against carbapenem-resistant bacteria.