Computational screening of T-muurolol for an alternative antibacterial solution againstStaphylococcus aureusinfections: A state-of-the-art phytochemical-based drug discovery approach
Authors: Bhattacharya Soham , Khanra Pijush Kanti , Dutta Adrish , Gupta Neha , Tehrani Zahra Aliakbar , Severová Lucie , Šrédl Karel , Dvořák Marek , Fernandez-Cusimamani Eloy 
Published: June 2024

AbstractStaphylococcus aureusinfections 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 variousS. aureusinfections. Hence, in this study, we have screened T-muurolol for possible interactions with severalS. 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 ofS. aureuslipase, dihydrofolate reductase, penicillin-binding protein 2a, D-Ala:D-Ala ligase, and RPP TetM, which indicates its potentiality againstS. aureusand 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-LUMOenergy 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 againstS. aureus. This study also suggests further clinical research before human application.Author SummaryStaphylococcus aureussignificantly contributes to human mortality, with over 1 million deaths annually accredited to its infections. At the same time, antimicrobial resistance (AMR) is a critical public health issue, responsible for an estimated 1.27 million deaths globally in 2019. The overuse and abuse of antimicrobials in both human and veterinary medicine are primary drivers of AMR, complicating the treatment of infections and increasing the risks associated with surgeries and other medical events. Despite the availability of antimicrobials such as methicillin, vancomycin, daptomycin, and linezolid, the emergence of multidrug-resistantS. aureusposes a formidable challenge to effective treatment. Due to the limited efficacy and increasing resilience to current antibiotics, there is an urgent need to discover new and effective antibacterial drugs againstS. aureus. Since time immemorial, phytochemicals have been valued for their rich biological properties and safety in treating bacterial infections. In this study, we have computationally investigated T-muurolol as a potential alternative antibacterial agent. Our molecular docking and simulation approaches provide insights into the interactions of T-muurolol as an inhibitor ofS. aureus-specific bacterial proteins. Additionally, pharmacokinetic and quantum chemical structure analyses offer valuable information about T-muurolol’s potential as a drug candidate, supporting its further development as an antibacterial agent.