Enhanced antibacterial activity of antimicrobial peptide—antibiotic combinations against multidrug-resistant bacteria

Abstract The rapid emergence of multidrug-resistant (MDR) bacteria has severely compromised the efficacy of conventional antibiotics and intensified the global antimicrobial resistance crisis. Antimicrobial peptides (AMPs) have attracted considerable interest as adjunctive agents due to their membrane-active mechanisms and immunomodulatory properties; however, their clinical use as monotherapy remains limited by instability, toxicity, and pharmacokinetic constraints. Combining AMPs with conventional antibiotics has emerged as a promising strategy to enhance antibacterial efficacy, restore antibiotic susceptibility, and modulate resistance development. This review critically examines the mechanistic basis of AMP–antibiotic synergy, integrating evidence from in vitro and in vivo studies. Particular emphasis is placed on determinants that govern synergistic outcomes, including membrane permeability, porin-dependent antibiotic uptake, resistance-associated adaptations, and host-related factors that cannot be captured in vitro. In addition, we discuss key translational barriers limiting clinical implementation, such as immune modulation, pharmacokinetic mismatch, peptide instability, and strain-dependent variability in synergistic responses. By linking molecular mechanisms to experimental and translational outcomes, this review provides a focused framework for rational design and optimization of AMP–antibiotic combination therapies against MDR bacterial infections.