Cheminformatics identification of phenolics as modulators of penicillin binding protein (PBP) 5 of Enterococcus faecium towards interventive antibacterial therapy

Penicillin-binding protein 5 (PBP5) of Enterococcus faecium is a high molecular mass protein crucial for the synthesis of peptidoglycan, a key component of the bacterial cell wall. This protein has garnered significant attention as a major therapeutic target due to its reported ability to reduce affinity for commonly prescribed β-lactams, leading to persistent antibiotic resistance. Consequently, bioprospection for new chemical entities with novel mechanisms of action against PBP5 of E. faecium remains one of the viable strategies to address this persistent menace. This study involved bioprospection of 1225 phenolics against the binding domain of PBP5, and the top five phenolics with best docking scores, acceptable pharmacokinetic attributes, and synthetic traits were further thermodynamically evaluated via a 200-ns molecular dynamics simulation period. Ph92237944, with the least docking score also showed a better binding affinity (-19.7 kcal/mol) for PBP5 relative to the reference standard [ampicillin (-12.31kcal/mol)]. In addition, post-dynamic evaluation showed Ph92237944 exhibited strong affinity and stability within the binding region of PBP5, as evidenced by stable hydrogen bonds, Van der Waals forces, and hydrophobic interactions. These interactions contributed significantly to the overall stability and affinity of the Ph92237944-PBP5 complex. Therefore, based on this finding, Ph92237944 has the potential to interact with and modulate the activity of low-affinity PBP5 of E. feacium , highlighting its potential for further investigation as a prospective antibacterial agent, pending experimental validation [ 1 ] [ 2 ] [ 3 ]. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany