The anti-MRSA efficacy of pyrrolomycin 5 by targeting membrane and in vivo therapeutic efficacy for MRSA-infected wound repair

The emergence and spread of methicillin-resistant Staphylococcus aureus (MRSA) represent a critical global health threat, heightened by widespread antibiotic overuse during the COVID-19 pandemic. The urgent situation drives the critical appealing discover novel, efficient, and non-toxic anti-MRSA drugs. This study initiated with screening natural products from Lingnan's characteristic medicinal plants and bacteria, leading to the identification of a pyrrolomycin-type compound, pyrrolomycin 5 (PM5). PM5 exhibited potent anti-MRSA activity with a minimum inhibitory concentration (MIC) of 0.78 μg/mL, comparable to that of vancomycin. It also demonstrated broad-spectrum efficacy against Gram-positive bacteria with a low propensity for resistance development. Mechanistic studies indicated that PM5 initially embeds into and depolarizes the bacterial membrane upon contact. As the concentration increases, PM5 accumulates on the membrane, ultimately compromising its integrity, causing rupture, and leading to bacterial cell death via leakage of cellular contents. The safety of PM5 was evaluated through in vitro cytotoxicity tests, and it was successfully applied in the treatment of skin infections in mice. In conclusion, PM5 represents a promising lead compound with a novel membrane-disrupting mechanism. This study provides valuable insights into its anti-MRSA mechanism and therapeutic efficacy. The findings offer a significant foundational framework for further development of pyrrolomycin-based antibiotics.