Identifying and Prioritizing Potential Inhibitors Targeting MurN in Enterococcus faecalis V583: A Promising Strategy for Combating Antibiotic Resistance

Enterococcus faecalis V583 commonly resides in the gastrointestinal (GI) tract of humans and animals, posing a growing threat to public health due to its increasing antibiotic resistance. Peptidoglycan is an essential cell wall component, which is constructed from repeating units comprising disaccharide, stem, and bridge components, where N ‐acetylglucosamine (GlcNAc) and N ‐acetylmuramic acid (MurNAc) are linked by a β (1–4) glycosidic bond. Fem AB family proteins, or alanine‐adding enzymes (MurM and MurN), are crucial in peptidoglycan biosynthesis and facilitate the incorporation of the first and second amino acids (L‐alanine) onto lipid II substrates. Targeting MurN is critical for combating antibiotic resistance, as it disrupts bacterial cell wall formation, potentially offering selective antimicrobial therapy. Together with the results obtained from molecular docking, virtual high‐throughput screening, molecular dynamics simulations, and MM/PBSA‐based binding free energy analysis, this study identifies five candidate inhibitors (Z327086474, Z905795966, Z1230302924, Z1239122011, and Z1636280945) for MurN based on their physiochemical, Lipinski’s drug‐like, ADMET, and structural properties. Z1636280945 (−74.43 kcal/mol) and Z905795966 (−65.74 kcal/mol) emerged as the top lead candidates for further experimental studies.