Antibacterial Potential of Ethyl 3,5-Dibromoorsellinate, a Derivative of Diphenyl Ethers from <i>Graphis handelii</i>, against Methicillin-Resistant <i>Staphylococcus aureus</i>

<i>Staphylococcus aureus</i> is a human pathogen responsible for a variety of diseases, from skin, soft tissue, and lung infections to severe cases such as meningitis, infective endocarditis, and bacteremia. The high level of antibiotic resistance in these pathogens, exemplified by methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), necessitates the development of effective antibiotics. Thus, this work introduced the chemical synthesis of ethyl 3,5-dibromoorsellinate, a derivative of ethyl orsellinate from the lichen mycobiont of <i>Graphis handelii</i>, and its effectiveness against MRSA was assessed. Results showed that ethyl 3,5-dibromoorsellinate efficiently inhibited MRSA with a minimum inhibitory concentration (MIC) of 4 μg/mL, and the time-kill analysis showed the bactericidal effect of ethyl 3,5-dibromoorsellinate on MRSA at 8× MIC after 24 h. The compound also exhibited selective activity against MRSA compared with the human cell line, with a selectivity index of 12.5-fold. While ethyl 3,5-dibromoorsellinate exhibited an indifferent effect with ampicillin, this compound demonstrated antagonistic effects with kanamycin in the synergistic assessment. Additionally, ethyl 3,5-dibromoorsellinate demonstrated antibiofilm activity against MRSA starting from 0.25× MIC. The molecular docking investigation illustrated that ethyl 3,5-dibromoorsellinate binds with the penicillin-binding protein 2A of MRSA with a free energy of -42.5 to -45.7 kcal/mol. Given its promising antibacterial activities, ethyl 3,5-dibromoorsellinate warrants further investigation as a potential antibiotic option against MRSA.