Peptide-based antibiotics: structure-driven strategies to tackle toxicity and resistance of antimicrobial peptides

Antimicrobial peptides (AMPs) are a prominent weapon that can expand human beings' arsenal against antimicrobial resistance. However, microorganisms can equip themselves against the antimicrobial effects of AMPs. Increasing daily dosing of AMPs to dispel resistance may lead to severe side effects or toxicity. In addition, some poor properties of AMPs, such as rapid degradation and low water solubility, make it difficult to achieve the right therapeutic dose at the target site. To provide more potent and less toxic AMPs, structural modification is one of the promising approaches. This review focuses on five representative AMPs: daptomycin, pexiganan (MSI-78), murepavadin (POL7080), iseganan (IB-367), and omiganan (MBI-226), and involves an analysis of their clinical development, mechanisms of resistance, toxicity profiles, and resultant outcomes. By investigating these specific cases, we derive critical insights into the factors influencing the emergence of resistance, the challenges posed by toxicity, and the structural limitations that have impeded the translation of AMPs into clinical applications. Furthermore, we discuss prospective peptide design strategies that may effectively address these challenges. Notably, we underscore the potential of structure-based strategies, including amino acid substitutions and conjugation with diverse molecular entities (such as small functional groups, synthetic polymers, peptides, and antibiotics), as promising pathways to mitigate these barriers and advance the development of clinically viable AMP therapeutics.