Identification of Potential Inhibitors for Beta-Lactamase in Methicillin- Resistant Staphylococcus aureus from Flavonoids Using a Computational Drug Discovery Approach

Background: Staphylococcus aureus (S. aureus) is a Gram-positive bacterium causing a wide range of human infections, leading to life-threatening invasive disorders, hospitalization, and mortality. Producing β-lactamase enzymes in S. aureus is one of the main mechanisms of the pathogen that makes the bacteria resistant to beta-lactam antibiotics, resulting in methicillin-resistant S. aureus (MRSA) strains. Therefore, it is crucial to identify novel β-lactamase inhibitors to combat infections caused by MRSA strains. Methods: In silico virtual screening approach was executed to evaluate the binding affinity of several natural flavonoids to the MRSA β-lactamase active site. After that, the stability of interactions between top inhibitors and the residues incorporated inside the β-lactamase was examined by molecular dynamics (MD) simulation. Moreover, the most connected amino acid within the catalytic domain of the enzyme was determined. Results: Rutin, isoquercitrin, nicotiflorin, quercetin-3-rhamnoside, vicenin-2, quercitrin, and orientin demonstrated a salient binding affinity with the β-lactamase active site (ΔG binding < −10 kcal/mol). Interestingly, the inhibition constant value (Ki) for rutin was estimated at the picomolar scale. The docked poses of these compounds were demonstrated to be stable. Moreover, Gln237 was revealed to be the most crucial residue involved in ligand binding. Conclusion: Rutin, isoquercitrin, nicotiflorin, quercetin-3-rhamnoside, vicenin-2, quercitrin, and orientin may be potent inhibitors of β-lactamase and may be helpful for the treatment of several invasive infections caused by MRSA strains. However, experimental studies are needed in the future to validate our findings.