Molecular Engineering Enhances Antimicrobial Peptide Selectivity and Reduces Cytotoxicity Against Drug-Resistant Pathogens

The global rise of antimicrobial resistance poses an urgent threat, rendering conventional antibiotics increasingly ineffective. This crisis necessitates the development of novel therapeutic alternatives. Antimicrobial peptides (AMPs) represent a promising class of agents due to their broad-spectrum activity, rapid action, and low propensity for resistance development. However, their clinical translation is often hampered by issues such as host cell cytotoxicity, poor stability, and inadequate selectivity, creating a critical gap in their therapeutic potential.

This comprehensive review synthesizes recent progress in engineering antimicrobial peptides (AMPs) to optimize their effectiveness by enhancing selectivity for treating infections while minimizing cytotoxicity to host cells. It explores the mechanisms by which AMPs exert their effects, including membrane disruption, intracellular targeting, biofilm inhibition, and immune modulation. The review details how physicochemical properties (e.g., charge and hydrophobicity), peptide length, and secondary structure influence both antimicrobial activity and host compatibility. An overview is provided of new design approaches, such as peptide modifications, peptide mimetic structures, hybrid peptides, dendritic AMPs, and the integration of computational methods and bioengineering techniques.

The review highlights that AMPs primarily function through mechanisms like disrupting bacterial membranes, targeting intracellular components, inhibiting biofilm formation, and modulating the host immune response. It emphasizes that optimizing physicochemical properties, such as net charge and hydrophobicity, along with peptide length and secondary structure, is crucial for enhancing antimicrobial activity while simultaneously reducing host cell toxicity. For instance, specific modifications can increase the therapeutic index by improving bacterial membrane specificity over eukaryotic membranes. > New engineering strategies, including hybrid peptides and peptide mimetics, demonstrate significant promise in overcoming challenges related to AMP stability, toxicity, and delivery, paving the way for more effective therapeutic agents. Computational methods are increasingly vital for predicting optimal peptide designs and screening candidates with enhanced selectivity and reduced cytotoxicity.