Discovery of Natural Magnolol/Dunnianol Inspired Derivatives as Potent Antibacterials against Methicillin-Resistant <i>Staphylococcus aureus</i>

Drug resistance and toxicity have made methicillin-resistant Staphylococcus aureus (MRSA) a major threat to livestock, creating an urgent need for novel anti-MRSA agents that are potent, safe, and less prone to resistance. Using magnolol and dunnianol as leads, we developed anti-MRSA derivatives. Bioactivity screening identified derivative 5c as the most promising candidate, exhibiting MICs of 1–2 μg/mL against standard and clinical MRSA strains, low hemolysis (HC 50 = 129.66 μg/mL), and a high selectivity index (64.83). Mechanistically, 5c rapidly disrupted bacterial membrane integrity, causing content leakage, out-performing vancomycin in speed, showing no resistance tendency, and exhibiting good plasma stability. 5c also demonstrated low cytotoxicity and no adverse effects on liver, kidney, or hematopoietic function in mice. In a murine MRSA skin infection model, 5c reduced abscess size and alleviated inflammation comparable to vancomycin, but without nephrotoxicity. Overall, 5c is a promising anti-MRSA agent for animal husbandry.