Identification of Phytochemical Inhibitors Targeting the hylEfm Gene in Multidrug-Resistant Enterococcus faecium Using Different Approaches

Enterococcus faecium, a significant nosocomial pathogen, has emerged as a critical global health threat due to its increasing resistance to conventional antibiotics, particularly vancomycin. This study focuses on the identification of a phytochemical-based drug candidate targeting the antibiotic-resistance gene hylEfm, which encodes a putative glycoside hydrolase protein in E. faecium, using in silico methods. The physicochemical properties of the protein, determined using ExPASy, suggested that the protein is stable. Protein flexibility analysis using CABS-flex 2.0 indicated acceptable structural dynamics. We selected 30 phytochemicals from PubChem and screened them against the putative glycoside hydrolase protein. Epigallocatechin (EGC) emerged as the lead candidate, demonstrating a binding energy of −7.4 kcal/mol and strong interactions with the protein. EGC physicochemical and pharmacokinetic properties, including high absorption, good water solubility, and low predicted toxicity, were evaluated using SwissADME and ProTox (version consistent with the manuscript). Molecular dynamics simulation suggested stability of the protein–ligand complex with an average root mean square deviation (RMSD) of 2.5 Å, root mean square fluctuation (RMSF) values of 1–2 Å, and a radius of gyration (R_g) ranging from 26.30 to 27.40 Å, indicating a compact structure. Molecular mechanics/generalized born surface area (MM/GBSA) and molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) energies of −34.5737 and −4.982 kcal/mol, respectively, indicate favorable electrostatic interactions between the glycoside hydrolase protein and EGC. Overall, the results indicate EGC as a promising and potentially safe drug candidate for targeting MDR E. faecium; however, these findings require in vitro and in vivo validation.