The emergence of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant global public health challenge due to its resistance to conventional antibiotics, primarily mediated by the mutated penicillin-binding protein, PBP2a. This study aims to investigate the potential of phytochemicals derived from medicinal plants in the Indian subcontinent to serve as adjuvants, enhancing the efficacy of methicillin against MRSA through allosteric modification of PBP2a using molecular docking and molecular dynamics (MD) simulation. After comprehensive Absorption, Distribution, Metabolism, and Excretion (ADME) profiling, along with AMES and hepatotoxicity tests, 9 compounds were shortlisted as suitable adjuvant candidates. Among them, nimbolide, quercetin, emodin, daidzein, eriodictyol, luteolin, and apigenin exhibited strong binding affinity to the allosteric site of PBP2a, with docking scores ranging from −8.7 to −7.3 kcal/mol. These phytochemicals facilitated enhanced methicillin binding, as evidenced by improved docking scores ranging from −6.1 to −6.8 kcal/mol, compared to −5.6 kcal/mol for methicillin alone. Molecular dynamics simulations confirmed the stability and favorable conformations of phytochemical-PBP2a complexes. Quercetin and daidzein were identified as the most promising adjuvant candidates, forming stable and energetically favorable complexes with PBP2a. Experimental validation showed that quercetin, at 30 mg/mL, effectively retained methicillin's antibacterial efficacy against MRSA. This study underscores the potential of natural compounds in overcoming antibiotic resistance and suggests that phytochemical-antibiotic synergism could be a viable strategy to combat multidrug-resistant bacterial infections. © 2024 Elsevier Ltd
