Broad-Spectrum Antimicrobial Efficacy of Cyclic Antimicrobial Peptide Against Multidrug-Resistant Staphylococcus aureus Infections

The increasing emergence and spread of multidrug-resistant (MDR) bacteria have intensified the search for novel antimicrobial peptides (AMPs). Here, we developed SAP 2.8 a synthetic amphipathic helical peptide, with the sequence "RCWKRWWRWWKRCWR", that demonstrates potent antibacterial activity, antibiofilm properties, and a well-characterized mechanism of action. SAP 2.8 peptide demonstrated a remarkable antibacterial effect against MDR Staphylococcus aureus (S. aureus) and Methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates, with minimum inhibitory concentrations (MICs) ranging from 1.25 to 2.5 μg/mL. It also demonstrated rapid bactericidal properties, eliminating pathogens within 30 min, while maintaining low cytotoxicity toward mammalian cells. SAP 2.8 effectively inhibited bacterial biofilm formation and disrupted preformed biofilms. Mechanistic studies revealed that the peptide induces membrane rupture and permeabilization, triggering increase intracellular reactive oxygen species production, ultimately resulting in bacterial death. Notably, SAP 2.8 significantly reduced bacterial load in animal models, positioning it as a promising candidate for the treatment of Gram-positive bacterial infections.