Bhattacharya, S.; Khanra, P. K.; Dutta, A.; GUPTA, N.; Tehrani, Z. A.; Severova, L.; Sredl, K.; Dvorak, M.; Cusimamani, E. F.; Cusimamani, E. F.

Staphylococcus aureus infections present a significant threat to the global healthcare system. The increasing resistance to existing antibiotics and their limited efficacy underscores the urgent need to identify new antibacterial agents with low toxicity to effectively combat various S. aureus infections. Hence, in this study, we have screened T-muurolol for possible interactions with several S. aureus-specific bacterial proteins to establish its potential as an alternative antibacterial agent. Based on binding affinity and interactions with amino acids T-muurolol was identified as a potential inhibitor of S. aureus lipase, dihydrofolate reductase, penicillin-binding protein 2a, D-Ala:D-Ala ligase, and RPP TetM, which indicates its potentiality against S. aureus and its multi-drug resistant strains. Also, T-muurolol exhibited good antioxidant and anti-inflammatory activity by showing strong binding interactions with FAD-dependent NAD(P)H oxidase, and cyclooxygenase-2. Consequently, MD simulation and recalculating binding free energies elucidated its binding interaction stability with targeted proteins. Furthermore, quantum chemical structure analysis based on density functional theory (DFT) depicted a higher EHOMO-LUMO energy gap with a lower chemical potential index, and moderate electrophilicity suggests its chemical hardness and stability and less polarizability and reactivity. Additionally, pharmacological parameters based on ADMET, Lipinski\'s rules, and bioactivity score validated it as a promising drug candidate with high activity toward ion channel modulators, nuclear receptor ligands, and enzyme inhibitors. In conclusion, the current findings suggest T-muurolol as a promising alternative antibacterial agent that might be a potential phytochemical-based drug against S. aureus. This study also suggests further clinical research before human application.