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

## TL;DR

Combining antimicrobial peptides with antibiotics may offer a new way to fight drug-resistant bacteria by enhancing treatment effectiveness.

## Contribution

The paper reviews the mechanisms and outcomes of combining antimicrobial peptides with antibiotics to combat multidrug-resistant bacteria.

## Key findings

- AMPs combined with antibiotics can enhance antibacterial efficacy and restore antibiotic susceptibility.
- Synergy depends on factors like membrane permeability and porin-dependent antibiotic uptake.
- Translational barriers include immune modulation and pharmacokinetic mismatch.

## 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.

This article explores how combining natural antimicrobial peptides with conventional antibiotics offers a powerful new strategy to overcome drug resistance and improve treatment of multidrug-resistant infections.