Title:Identification of Potential Inhibitors for Beta-Lactamase in Methicillin-
Resistant Staphylococcus aureus from Flavonoids Using a Computational
Drug Discovery Approach
Volume: 20
Issue: 8
Author(s): Amirreza Abdollahian, Maryam Hazhirkamal, Mohammad Taheri, Fatemeh Nouri*Amir Taherkhani*
Affiliation:
- Research Center for Molecular
Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Pharmaceutical Biotechnology,
School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular
Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
Keywords:
Antibiotic, β-lactamase, flavonoid, infections, inhibitor, methicillin-resistant Staphylococcus aureus.
Abstract:
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.