Computational Studies and Functional Validation of Eugenol and Ferulic Acid as Inhibitors of Against Enterococcus faecalis Sortase A

Abstract

Enterococcus faecalis (E. faecalis) is commonly occurring pathogen associated with nosocomial infections. Infections are difficult to treat because of their multidrug-resistant (MDR) nature and their tendency to form biofilms. Therefore, it is essential to find alternative medicinal approaches to treatment. In this regard, targeting an important protein for drug development can be an alternative approach. Sortase A (SrtA) is an important enzyme involved in anchoring cell surface-exposed proteins to the cell envelope. SrtA is present in Gram-positive bacteria which catalyses the attachment of several virulence factors and other proteins to the cell membrane. It is involved in bacterial pathogenesis, therefore, it's a promising drug target for the development of anti-microbial drugs targeting cell adhesion, evasion, and biofilm development. To identify SrtA potential inhibitors, we have expressed and purified E. faecalis Sortase A (EfSrtA_ΔN59). Structural studies using homology modelling along with molecular docking of protein with selected ligand molecules were also done. The results were confirmed by MD simulation experiments. We have also performed functional validation of these compounds on bacterial growth, anti-biofilm assays and inhibition assays of selected ligands were also done against E. faecalis individually and in synergistic combinations. Results indicated that both Eugenol and Ferulic acid bind to EfSrtA_ΔN59 with significant interactions and show promising results.