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 its 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 ribosome protection proteins tetracycline resistance determinant (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 flavin adenine dinucleotide (FAD)-dependent nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, and cyclooxygenase-2. Consequently, molecular dynamics (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 energy gap between the highest occupied molecular orbital and lowest unoccupied molecular orbital (EHOMO-LUMO) 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.

Department of Agroecology and Crop Production Faculty of Agrobiology Food and Natural Resources Czech University of Life Sciences Prague Kamýcká 129 Suchdol 16500 Prague Czech Republic

Department of Biosciences and Bioengineering Indian Institute of Technology Guwahati Guwahati 781039 India

Department of Crop Sciences and Agroforestry Faculty of Tropical AgriSciences Czech University of Life Sciences Prague Kamýcká 129 Suchdol 16500 Prague Czech Republic

Department of Economic Theories Faculty of Economics and Management Czech University of Life Sciences Prague Kamýcká 129 16500 Prague Czech Republic

Department of Trade and Finance Faculty of Economics and Management Czech University of Life Sciences Prague Kamýcká 129 16500 Prague Czech Republic

Institute of Biotechnology of the Czech Academy of Sciences BIOCEV Prumyslova 595 25250 Vestec Czech Republic

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