Combating the post-antibiotic era crisis: antimicrobial peptide/peptidomimetic-integrated combination therapies and delivery systems

Globally, new antibiotic development lags behind the rapid evolution of antibiotic-resistant bacteria. Given the extensive research and development cycles, high costs, and risks associated with new pharmaceuticals, exploring alternatives to conventional antibiotics and enhancing their efficacy and safety is a promising strategy for addressing challenges in the post-antibiotic era. Previous studies have shown that antimicrobial peptides/peptidomimetics (AMPs) primarily use a membrane-disruption mechanism distinct from conventional antibiotics to exert bactericidal effects. They exhibit broad-spectrum antibacterial activity, lower risk of drug resistance, and effectiveness against multidrug-resistant strains, making them promising alternative antimicrobials. This review adopts a synergistic therapeutic strategy perspective, initially examining the structure-dependent multimodal antimicrobial mechanisms of AMPs. Then, the advantages of AMP-integrated combination therapies over monotherapies are analyzed, alongside technological advancements in various drug delivery systems (e.g., nanoparticles, hydrogels, microneedle patches, and inhaled formulations) that enhance targeting, prolong therapeutic efficacy, and reduce systemic toxicity. Finally, this study comprehensively analyzes the synergistic effects and delivery system designs of AMPs combined with small-molecule adjuvants (e.g., antibiotics, quorum sensing inhibitors) and nanomaterials (e.g., metal nanoparticles, photoresponsive materials) with case studies from recent literature. This review aims to promote the clinical translation of AMPs and offer new insights to address the global drug-resistance crisis.