Computational identification of novel anti-methicillin resistant Staphylococcus aureus agents by screening Traditional Chinese Medicine (TCM) library against penicillin-binding protein 2a (PBP2a): A study of molecular docking, dynamics simulation and in vitro antimicrobial activity

The improper and wide use of antibiotics are driving the emergence of resistant bacterial strains. Of these emergent strains, the methicillin-resistant S. aureus (MRSA) is considered a public health threat that can increase both treatment duration and cost. Currently, MRSA strain has developed resistance to many penicillins and cephalosporins due to the expression of insensitive penicillin-binding protein 2a (PBP2a). This transpeptidase variant, PBP2a, has a low binding affinity toward β-lactam ring. Thus, the acquisition of PBP2a can confer resistance for MRSA against the bactericidal effect of penicillin and cephalosporin antibiotics. As such, the active site of PBP2a enzyme is now regarded as a potential molecular target to develop new anti-MRSA therapeutics. However, the pace of developing new antimicrobial agents is still much slower than the rate of bacterial resistance evolution. Also, many of the available antibiotics were developed from microbial sources but the herbal sources are yet to be explored. Therefore, the aim of this in-silico study is to virtually screen a library of Traditional Chinese Medicine (TCM) compounds against the active site of PBP2a to identify possible anti-MRSA phytomedicines. For this purpose, both molecular docking and dynamics simulation were employed in this study. Moreover, agar well diffusion method was used to assess the in vitro antimicrobial activity of final hit compounds against MRSA cultured colonies. The results of molecular dynamics (MD) study indicate that both sciadopitysin and plantamajoside can maintain a close proximity to PBP2a active site during 50 nanoseconds simulation. During this simulation, the average ligand movement root mean square deviation (RMSD) was 3.17 and 3.00 Angstrom for sciadopitysin and plantamajoside respectively. Additionally, the most preferred molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) binding energy was reported to be -24.09 Kcal/ mol for sciadopitysin. While docking study results point to the possible hydrogen bond interaction of sciadopitysin and plantamajoside with Serine 403 active site residue. However, sciadopitysin is predicted to be engaged in two hydrogen bonds with the nucleophile Serine 403 residue as compared to only one hydrogen bond in case of plantamajoside. Also, the length of these hydrogen bonds seems to be shorter when considering the interaction of sciadopitysin with Serine 403 residue. Further, the agar well diffusion study refers to the fact that both sciadopitysin and plantamajoside are effective in inhibiting the growth of MRSA culture with a measured zone of inhibition: 12.5 ± 0.7 and 9.0 ± 1.4 mm respectively. In conclusion, it is predicted that the phenolic compounds sciadopitysin and plantamajoside from TCM library are potential inhibitors to PBP2a enzyme. These two phytomedicines can represent possible candidates to develop new anti-MRSA agents. However, additional modifications to these compounds’ physicochemical characteristics are required to improve their drug-likeness and pharmacokinetics.