Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study

Abstract

Recently, the interest in plant-derived antimicrobial agents has increased. However, there are no sufficient studies dealing with their modes of action. Herein, we investigate an in-house library of common plant-based phenolic compounds for their potential antibacterial effects against the methicillin-resistant Staphylococcus aureus (MRSA), a widespread life-threatening superbug. Flavonoids, which are considered major constituents in the plant kingdom, were found to be a promising class of compounds against MRSA, particularly the non-glycosylated ones. On the other hand, the glycosylated derivatives, along with the flavonolignan silibinin A, were able to restore the inhibitory activity of ampicillin against MRSA. To explore the mode of action of this class, they were subjected to an extensive inverse virtual screening (IVS), which suggested penicillin-binding protein 2a (PBP2a) as a possible target that mediates both the antibacterial and the antibiotic-synergistic effects of this class of compounds. Further molecular docking and molecular dynamic simulation experiments were conducted to support the primary IVS and the in vitro results and to study their binding modes with PBP2a. Our findings shed a light on plant-derived natural products, notably flavonoids, as a promising and readily available source for future adjuvant antimicrobial therapy against resistant strains.

Flavonoid-Coated Gold Nanoparticles as Efficient Antibiotics against Gram-Negative Bacteria—Evidence from In Silico-Supported In Vitro Studies

“…As shown in Figure 1 , some of the tested flavonoids showed weak millimolar activity and some of them were inactive up to 1 mM. However, in our previous report, we found that some of these flavonoids (e.g., chrysin and apigenin) were far more active against Gram-positive bacteria (e.g., Staphylococcus aureus ), where their minimum inhibitory concentrations (MICs) were in the micromolar range [ 14 ]. These significant differences in the antibacterial activity could be attributed to the Gram-negative bacterial outer membrane, which usually acts as a natural protective barrier preventing the passage of unfavourable compounds [ 15 ].…”

“…As a part of the continuing investigation into safe and effective antibacterial agents from natural products, a number of non-glycosylated flavonoids have been tested for their growth inhibitory activity against some Gram-negative bacteria ( Escherichia coli , Pseudomonas aeruginosa , Proteus vulgaris and Klebsiella pneumonia ). This class of compounds has been found to exert antibacterial activity via multiple mechanisms: (i) altering the fluidity of the bacterial membranes (i.e., increasing their rigidity), an effect that was found to be associated with bacterial growth inhibition [ 12 ]; (ii) inhibiting DNA gyrase and, in turn, bacterial DNA supercoiling [ 13 ]; and (iii) inhibiting the bacterial penicillin-binding proteins (PBPs) and thus inhibiting bacterial cell wall biosynthesis [ 14 ].…”

Antibacterial Activity of Arbutus pavarii Pamp against Methicillin-Resistant Staphylococcus aureus (MRSA) and UHPLC-MS/MS Profile of the Bioactive Fraction

“…In addition, several studies have shown that the effectiveness of β-lactams can be enhanced by combining them with epigallocatechin gallate [ 45 , 46 ] and epicatechin gallate [ 47 ]. Meanwhile, Su et al [ 48 ] reported that quercetin exhibited inhibitory effect against different MRSA strains, with MIC values ranging from 31.25 to 125 μg/mL, while rutin, a quercetin-3- O -deoxyhexosylhexoside, was reported to inhibit MRSA with MIC value of 250 μg/mL [ 49 ]. Besides, arbutin was reported to exert antibacterial activity against MRSA with MIC value of 10 mg/mL and MBC value of 20 mg/mL [ 50 ].…”

Sinapic Acid Suppresses SARS CoV-2 Replication by Targeting Its Envelope Protein

“…For further confirmation of the initial docking and MDS experiments, we generated a binding event simulation by placing the ligand close to the E-protein’s binding site (21 Å away from ASN-15) and applying force (10 kcal/mol · A 2 ) toward its center to make SA move toward the binding site with a velocity of 0.31 Å/ns. Finally, generated trajectories were visualized and analyzed by VMD software [ 36 , 37 ].…”