Advancing antimicrobial peptides: Mechanisms, design, and applications in the post-antibiotic era

The rapid emergence of multidrug-resistant and extensively drug-resistant bacteria has intensified the need for alternative antimicrobial strategies in the post-antibiotic era. Antimicrobial peptides (AMPs), as evolutionarily conserved components of innate immunity, have attracted considerable attention due to their broad-spectrum antimicrobial activity, rapid mechanisms of action, and lower propensity for resistance development. This review summarizes the structural diversity, mechanisms of action, and structure-activity relationships (SAR) of AMPs that underpin their biological activity and guide the rational design of next-generation peptide therapeutics. It further discusses recent advances in peptide engineering, peptidomimetic design, machine learning-assisted discovery, innovative production platforms, and the application of CRISPR-Cas genome editing for production host optimization. In addition, the review highlights synergistic therapeutic strategies, current clinical progress, and the expanding applications of AMPs in medicine, food preservation, agriculture, and aquaculture. Despite these advances, challenges including limited stability, potential toxicity, manufacturing costs, and regulatory barriers continue to hinder widespread clinical translation of AMP-based therapeutics. By integrating recent experimental and computational advances with current translational challenges and future perspectives, this review provides a comprehensive overview of the field and highlights key directions for the rational development and clinical translation of next-generation antimicrobial peptides to combat antimicrobial resistance.