Antimicrobial peptides-based strategies at the frontline in battling the escalating menace of methicillin-resistant Staphylococcus aureus biofilms.

Antimicrobial resistance (AMR), particularly in methicillin-resistant Staphylococcus aureus (MRSA), continues to threaten global health due to its multidrug resistance and strong biofilm-forming ability. Antimicrobial peptides (AMPs) have emerged as promising agents against MRSA biofilms because of their diverse origins, structural versatility, and unique modes of action. Natural AMPs derived from animals, plants, fungi, protists, archaea, and bacteria primarily act by disrupting bacterial membranes, interfering with quorum sensing, and downregulating biofilm-related genes such as sarA, icaA, and icaD. Synthetic AMPs, designed through computational modeling and machine learning, demonstrate enhanced stability, reduced toxicity, and improved target specificity. Synergistic AMP-antibiotic combinations, including nisin, indolicidin, and α-MSH analogs with β-lactams, significantly improve antibiofilm efficacy and bacterial clearance. Despite these advances, challenges persist due to peptide instability, enzymatic degradation, cytotoxicity, and limited in vivo validation. Recent developments in nanoparticle, hydrogel, coatings, and nanofiber delivery systems have improved AMP bioavailability and controlled release within biofilms. Continued integration of peptide engineering, nanotechnology, and bioinformatics-driven design offers promising solutions for clinical translation. Overall, AMPs represent a frontier in combating MRSA biofilms and antibiotic resistance, with future research focusing on stability enhancement, resistance prevention, and optimized therapeutic delivery.