Quercetin 3-O-rutinoside mediated inhibition of PBP2a: computational and experimental evidence to its anti-MRSA activity

Abstract

The PBP2a is a cell wall synthesizing protein, which causes resistivity in methicillin resistant Staphylococcus aureus (MRSA) from β-lactam antibiotics but it is susceptible to 5th generation cephalosporin, ceftobiprole. Ceftobiprole inhibits the growth of MRSA by targeting the PBP2a-mediated cell wall synthesis, but it is reported to have adverse side effects. Due to this, there is a constant need to develop natural alternatives, which are generally free from adverse side effects. Hence in this study, in silico based docking analysis was performed with 37 quercetin derivatives towards PBP2a inhibition and their efficiencies were compared with β-lactam antibiotic, ceftobiprole. The docking studies suggested that quercetin 3-O-rutinoside (ZINC5280805) interacted efficiently with PBP2a, attaining the highest LibDock score (187.32) compared to other quercetin derivatives. The structural stability and dynamics of the identified lead with PBP2a were validated through molecular dynamics simulation. Simulation results such as RMSD, RMSF, and Rg values indicated that the stability of quercetin 3-O-rutinoside with PBP2a was better, with respect to the un-ligated PBP2a. Furthermore, the quercetin 3-O-rutinoside was subjected to an antibacterial susceptibility test and found to have antibacterial activity at 500, 700, and 900 μM concentration. Also, morphological changes in the bacterial colony and bacterial surface were observed using a scanning electron microscope, when MRSA was treated with 900 μM concentration of quercetin 3-O-rutinoside. Collectively, results from this study suggest that the quercetin 3-O-rutinoside has the capability to inhibit PBP2a and hence could be used as an alternative or in combination with other drugs in treating MRSA infection.

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“…[28] Quercetin demonstrated the highest inhibition potential toward PBP2a with a binding energy of −10.0 kcal/mol. It is notable that quercetin derivatives have already been reported to have antibacterial activity against MRSA bacteria by Rani et al [29] Since quercetin derivatives have already been proven for their in vitro anti-MRSA and anti-PBP2a activity, it supports the current prediction of quercetin being inhibitor of PBP2a. Inhibition of PBP2a would result in bactericidal activity, by disruption of the biosynthesis of bacterial cell wall.…”

Molecular docking and pharmacokinetic prediction of phytochemicals from Syzygium cumini in interaction with penicillin-binding protein 2a and erythromycin ribosomal methylase of Staphylococcus aureus

“…Because natural compounds are considered to be safe, nontoxic, and less prone to side effects (Rani et al, 2014 ), in the present study, naturally occurring phytochemicals from different plant sources were selected and validated for PBP2a inhibition in MRSA infection. Molecular docking analysis suggested that diferulic acid had a higher specificity toward the PBP2a binding site and thus caused inhibition of MRSA by inhibiting the biosynthesis of its cell wall (Rani et al, 2014 ). It is notable that the compound taxifolin exhibited antibacterial activity by hindering with the function of ERM in MLSB strains of S. aureus .…”

Phenolic profiling and antibacterial potential of Saudi Arabian native date palm (Phoenix dactylifera) cultivars

“…[30] Quercetin rutinoside detected in extract of Ajwa has been widely reported for their antibacterial activity. Rani et al [31] reveled the antibacterial potential of Quercetin 3-O-rutinoside against Staphylococcus aureus and they also observed changes in bacterial colonies and surface. Likewise, Alvarez et al, [32] also observed the antibacterial effect of quercitin-rutinoside against Staphylococcus aureus, Escherichia coli, and Enterobacter aerogenes.…”