Advances in Antimicrobial Peptides: Design, Mechanism, and Clinical Application-A Critical Review.

The global antimicrobial resistance (AMR) crisis, projected to cause 10 million deaths annually by 2050, necessitates innovative therapeutic strategies beyond traditional antibiotics. Antimicrobial peptides (AMPs), fundamental components of innate immunity, have emerged as compelling candidates owing to their broad-spectrum activity and mechanism of action, which challenges conventional resistance development. This review critically synthesizes the latest advances in the field, where the transition from natural discovery to rational engineering is of paramount importance. This review explores how computational design, artificial intelligence, and peptidomimetics can generate next-generation AMPs with enhanced stability and reduced toxicity. Furthermore, we dissected their multifaceted mechanisms, which extend beyond membrane disruption to include immunomodulation and intracellular targeting. However, the clinical pipeline reveals significant hurdles, with recent late-stage failures of candidates such as murepavadin and surotomycin, underscoring persistent challenges in systemic toxicity and pharmacokinetics. Looking ahead, we assess promising strategies to overcome these barriers, including AMP-antibiotic synergies and targeted delivery systems. This review aims to provide a realistic and forward-looking analysis of the design principles, mechanistic complexity, and translational potential of AMPs, framing their role in future antimicrobial strategies.