Engineered Hybrid Lantibiotic that Selectively Combats Infections Caused by Staphylococcus aureus

The rapid emergence of antibiotic-resistant strains of Staphylococcus aureus presents a substantial challenge to global public health, underscoring the urgent need for novel antibiotics with diverse mechanisms of action. In this study, we conducted mutagenesis on the C-terminal region of the lantibiotic ripcin C to enhance its antimicrobial efficacy against S. aureus. The resulting optimized variant, ripcin CP23A, demonstrated potent and selective antimicrobial activity, with a minimal inhibitory concentration of 2-4 mg/L against S. aureus. Beyond its strong antimicrobial properties, ripcin CP23A exhibited significant antibiofilm activity against methicillin-resistant S. aureus (MRSA). Mechanistic studies revealed that, in addition to targeting lipid II, ripcin CP23A disrupts bacterial membranes, a capability absent in ripcin C, which may contribute to its superior antimicrobial and antibiofilm effects. Moreover, ripcin CP23A displayed favorable biosafety and plasma stability profiles. Notably, in a mouse model of MRSA-induced mastitis, ripcin CP23A effectively reduced bacterial load, alleviated inflammation, and preserved the normal histomorphology of mammary glands. This study introduces ripcin CP23A as a promising antibiotic candidate for the treatment of MRSA-related infections.