Antimicrobial Peptides and Biofilms: From Molecular Interactions to Therapeutic Control

The rising problem of antimicrobial resistance (AMR), further complicated by the resilience of bacterial biofilms, calls for the discovery of new therapeutic strategies. Bacteria residing in biofilms rely on extracellular polymeric substance (EPS) scaffolds, quorum sensing (QS) circuits, and metabolic dormancy to protect themselves against standard antibiotics. Antimicrobial peptides (AMPs) have recently been recognized as a promising new class of antimicrobials, exploiting mechanisms of action that circumvent established resistance mechanisms. This review offers a comprehensive overview of AMPs as antibiofilm agents, integrating basic molecular principles with translational applications. We discuss the critical challenges imposed by the biofilm environment and demonstrate how both natural and designed AMPs overcome these barriers by disrupting EPS structure, quenching QS communication, and killing metabolically dormant persister cells. In addition to their use as monotherapies, we assess the synergistic benefits of innovative AMP-antibiotic combinations, nanoparticle-AMP conjugates, and surface-functionalized coatings that aim to improve the stability and therapeutic index of AMPs. Moreover, this review also points to the cutting-edge field of peptide engineering, where we emphasize the importance of artificial intelligence, machine learning, and multiomics approaches to expedite the in silico design of synthetic peptides.