Overcoming multidrug resistance: antimicrobial peptides as a next-generation therapeutic strategy

Amidst the escalating global threat of antibiotic resistance, there is an urgent need for novel antibacterial agents with distinct mechanisms of action to address the impending post-antibiotic era. Antimicrobial peptides (AMPs), membrane-active peptides characterized by rapid bactericidal effects, broad-spectrum activity, and low resistance development potential, are considered promising candidates for overcoming the current multidrug resistance (MDR) crisis. However, the clinical application of AMPs is significantly limited by inherent drawbacks, including susceptibility to proteolytic degradation, poor oral bioavailability, potential mammalian cytotoxicity, low in vivo efficacy, and high production costs. These limitations have spurred extensive efforts to redesign and modify AMPs based on their physicochemical properties and mechanisms. This review first summarizes four classical models describing the initial binding and membrane disruption processes of AMPs. It then focuses on recent advancements in the chemical synthesis and modification of AMPs, as well as AMP-based drug delivery systems. In conclusion, this review provides a comprehensive perspective on the mechanisms of action, progress in novel therapeutic strategies, and prospects for the clinical translation of AMPs.