Reframing Antimicrobial Peptides beyond Direct Antimicrobial Activity toward Host-Directed Functions and...

Antimicrobial peptides (AMPs) have been extensively investigated as alternatives to conventional antibiotics to combat multidrug-resistant bacteria. This narrow antibiotic-replacement framework underestimates the biological and translational potential of AMPs. The present review reframes them as disease-context-dependent therapeutic platforms rather than universal antibiotic substitutes. In particular, this review critically examines their microbiological basis, mechanisms of action, emerging applications, engineering strategies, formulation approaches, translational limitations, and criteria for translational development. AMPs exert diverse activities at the host-microbe interface. These effects include direct antimicrobial activity, membrane perturbation, intracellular targeting, antibiofilm effects, endotoxin neutralization, immunomodulation, and tissue repair. Hence, these multifunctional properties support their potential as therapeutic candidates for chronic wounds, biofilm-associated infections, device-related infections, mucosal and respiratory disorders, and inflammation-associated disorders. Furthermore, recent advances in peptide engineering, artificial intelligence-guided design, and delivery technologies, including nanocarriers, hydrogels, and surface immobilization, have expanded the design space and translational opportunities for AMPs. Major translational barriers remain, including cytotoxicity, hemolysis, proteolytic instability, resistance selection and cross-resistance, limited pharmacokinetic and pharmacodynamic characterization, manufacturing costs, scale-up challenges, and uncertain clinical positioning. Overall, AMPs should be developed through a translational decision matrix that integrates mechanism, microbial susceptibility, host response, formulation, safety, and disease-relevant efficacy rather than through antimicrobial potency ranking alone.