Antimicrobial Peptides as Antibiotic Adjuvants: Overcoming Resistance through Multifaceted Mechanisms

Antimicrobial resistance (AMR) has escalated into a major global health crisis, demanding alternative strategies beyond the discovery of new antibiotics. Antimicrobial peptides (AMPs) represent a promising class of adjuvant therapeutics capable of restoring or enhancing the activity of conventional antibiotics. Owing to their structural diversity and multifunctional mechanisms, AMPs can potentiate antibiotic efficacy through membrane permeabilization, disruption of biofilm architecture, inhibition of efflux pumps and β-lactamases, modulation of quorum sensing, and immune regulation. Recent advances show that rationally engineered peptides, synthetic derivatives, peptide hybrids, and transmembrane mimetic strategies can overcome both intrinsic and acquired resistance phenotypes across clinically relevant Gram-negative and Gram-positive pathogens. Furthermore, peptide adjuvants enable dose reductions of toxic antibiotics and can circumvent pathogen persistence, thereby improving both pharmacodynamic outcomes and therapeutic index. Nevertheless, major translational bottlenecks remain, including peptide instability, proteolytic susceptibility, toxicity, and limited in vivo validation. Peptide engineering, incorporation of D-residues, cyclization, conjugation with antibiotics, and advanced delivery systems such as nanoparticles and liposomal platforms are increasingly addressing these limitations. Collectively, this review highlights the therapeutic potential of peptide-antibiotic combinations as next-generation adjuvant therapies and emphasizes the need for integrative computational, chemical, mechanistic, and in vivo approaches to accelerate their clinical development.