Amphiphilic xanthotoxin derivatives with phosphatidylglycerol-targeting membrane disruption for potent...

With the escalating threat posed by methicillin-resistant Staphylococcus aureus (MRSA) infections, the development of novel and potent antibacterial agents is an urgent priority. Based on this rationale, xanthotoxin was employed as the lead structure, a series of derivatives were designed and synthesized, and their antibacterial potential was systematically evaluated. Compound H1 exhibited outstanding activity against S. aureus ATCC 29213, the MRSA reference strain N315, and nine clinical MRSA isolates (MIC = 1 μg/mL), along with low hemolysis, good plasma stability, low cytotoxicity, and a low tendency to induce resistance. H1 achieved rapid bactericidal action during the early stages of bacterial growth, and its killing rate and potency surpassed those of vancomycin at the same concentration. In the MRSA-infected mouse skin abscess model, H1 demonstrated remarkable in vivo antibacterial efficacy and excellent biosafety, with a therapeutic effect comparable to that of vancomycin. Mechanism studies further revealed that H1 mainly induced bacterial death by specifically interacting with the unique phosphatidylglycerol (PG) in the bacterial cell membrane, causing rapid depolarization of the membrane potential and disruption of membrane permeability, leading to the rupture of the cell membrane structure and leakage of intracellular contents. Taken together, H1 combines potent antibacterial activity with favorable safety profiles, highlighting its strong potential as a promising therapeutic candidate for treating MRSA infections.