In silico and in vitro studies of cinnamaldehyde and their derivatives against LuxS in Streptococcus pyogenes: effects on biofilm and virulence genes.

The LuxS-based signalling pathway has an important role in physiological and pathogenic functions that are capable of causing different infections. In the present study, cinnamaldehyde (CN) and their derivatives were evaluated for their inhibitory efficiency against LuxS by molecular modelling, docking, dynamics and free-energy calculations. Sequence and structure-similarity analysis of LuxS protein, five different amino acids were found to be highly conserved, of which GLY128 was identified as the key residue involved in the effective binding of the ligands. Quantum-polarized ligand docking protocol showed that 2nitro and 4nitro CN has a higher binding efficiency than CN, which very well corroborates with the in vitro studies. COMSTAT analysis for the microscopic images of the S. pyogenes biofilm showed that the ligands have antibiofilm potential. In addition, the results of quantitative polymerase chain reaction (qPCR) analysis revealed that the transcripts treated with the compounds showed decrease in luxS expression, which directly reflects with the reduction in expression of speB. No substantial effect was observed on the virulence regulator (srv) transcript. These results confirm that speB is controlled by the regulation of luxS. The decreased rate of S. pyogenes survival in the presence of these ligands envisaged the fact that the compounds could readily enhance opsonophagocytosis with the reduction of virulence factor secretion. Thus, the overall data supports the use of CN derivatives against quorum sensing-mediated infections caused by S. pyogenes.