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| Autores principales: | , , , |
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| Formato: | Artículo Open Access |
| Publicado: |
Wiley
2026
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| Materias: | |
| Acceso en línea: | https://onlinelibrary.wiley.com/doi/10.1002/psc.70098 |
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- Rational Design and Biological Evaluation of Imidazole‐Based Tetrapeptides as Antibacterial Leads Against Staphylococcus aureus Mohammed Sharif Shaik Vidya Sagar Jerra Balajee Ramachandran Srinivasadesikan Venkatesan Journal of Peptide Science ABSTRACT The increasing prevalence of methicillin and vancomycin‐resistant Staphylococcus aureus (MRSA/VRSA) necessitates new antibacterial agents. Penicillin‐binding protein 2a (PBP2a) plays a crucial role in bacterial cell wall synthesis. In this work, 125 imidazole‐based tetrapeptides were rationally designed and evaluated in silico and experimentally. Molecular docking studies revealed binding energies from −6.6 to −4.0 kcal/mol against MRSA target. The six most promising compounds ( A–F ) were synthesized and screened against methicillin‐susceptible S. aureus (MSSA), MRSA and VRSA. Compound C showed the most promising antibacterial analogue with minimum inhibitory concentration (MIC) of 29.8 ± 4.2 μg/mL among the analogues. Time‐kill assays demonstrated bactericidal activity against MSSA and MRSA and bacteriostatic activity against VRSA. All compounds showed < 5% haemolysis, suggesting low toxicity. ADME predictions indicated favourable physicochemical properties and safety profiles. The molecular dynamics simulation (MDS) for compound C shows stable interactions with Ser403, Tyr446, Glu447, Ser462, Lys597, Ser598 and Thr600 key residues in the PBP2a active site. The DFT study confirms the stability of compound C in the PBP2a active site with a binding energy of −42.73 kcal/mol. Overall, compound C is a promising lead for anti‐ staphylococcal drug development; however, the mechanism of action requires further experimental validation. 10.1002/psc.70098 http://onlinelibrary.wiley.com/termsAndConditions#vor