Decoding antimicrobial peptides: An insight into their discovery, classifications, structures, and applications

The global public health sector is confronted with the intensifying issue of antimicrobial resistance, especially the advent of multi-drug-resistant, extensively drug-resistant, and pan-drug-resistant strains. These challenges have narrowed down current treatment options for bacterial infections, thereby calling for urgent strategies to curb the extension of bacterial resistance. The exploration of non-antibiotic alternatives plays a pivotal role in addressing the issue of drug resistance in the modern era. Antimicrobial peptides (AMPs) are considered as promising candidates for the next generation of antibiotic drugs, which mostly are cationic peptides that bind to negatively charged bacterial cell membranes, thereby disrupting the cellular morphology and causing bacterial death. In addition to extracellular targeting mechanisms, AMPs encompass intracellular targeting mechanisms and anti-inflammatory mechanisms. They can be employed both individually or in combination with other antibiotics to amplify the antibacterial effect. However, despite extensive preclinical investigation, the majority of AMP candidates have failed to translate into clinically viable therapeutics. In this review, particular attention is given to both clinical successes and failures, with an emphasis on the roles of pharmacokinetics, dosing constraints, and indication selection. We further evaluate the current impact and limitations of computational and AI-guided AMP design, highlighting the persistent gap between in vitro discovery and in vivo efficacy. By integrating mechanistic insights with clinical and developmental considerations, this review aims to provide a conceptual framework for understanding why most AMPs fail clinically and what principles may enable the development of translationally successful peptide-based antimicrobials.