# Natural and Synthetic Peptides as Alternatives to Antibiotics in Intestinal Infections—A Review

## TL;DR

This review explores how natural and synthetic peptides can serve as alternatives to antibiotics for treating intestinal infections, highlighting their effectiveness and lower resistance risks.

## Contribution

The paper systematically reviews the therapeutic potential of both natural and synthetic antimicrobial peptides for gastrointestinal infections, emphasizing their multifaceted mechanisms.

## Key findings

- Natural AMPs show antimicrobial and immunomodulatory effects against pathogens like E. coli and Salmonella.
- Synthetic peptides offer improved stability and synergistic interactions with antibiotics.
- AMPs preserve epithelial barrier integrity and limit inflammation in the gut.

## Abstract

Background/Objectives: Antimicrobial peptides (AMPs), evolutionarily conserved components of innate immunity characterized by their broad-spectrum efficacy and minimal resistance development, are increasingly recognized as promising therapeutic candidates. This review aims to integrate current knowledge concerning natural and synthetic antimicrobial peptides and their therapeutic effectiveness in addressing gastrointestinal infections. Methods: A literature review was performed, evaluating recent peer-reviewed studies on AMPs. The research concentrated on their molecular mechanisms of action, antimicrobial spectrum, and their interactions with standard antibiotics. More in detail, the peptide classes examined herein included defensins, cathelicidins, histatins, and various natural peptides such as lactoferricin, protamines, RegIII, and hepcidin, along with synthetic analogs like WR12, D-IK8, MSI-78, and IMX942. Results: Natural AMPs demonstrated significant antimicrobial and immunomodulatory effects against Escherichia coli, Klebsiella pneumoniae, Salmonella spp., and Shigella spp. Beyond direct antimicrobial activity, antimicrobial peptides act as integrated anti-infective agents not only by modulating host–microbiota interactions, but also preserving epithelial barrier integrity, and limiting inflammation, thereby offering a multifaceted strategy to control gastrointestinal infections. On the other hand, synthetic peptides showed improved stability, reduced cytotoxicity, and synergistic interactions with antibiotics, which suggests that they could be used either alone or in combination with other treatments. Conclusions: AMPs constitute a promising category endowed with anti-infective activity, especially for therapy of intestinal diseases, which is attributed to their distinctive anti-infective mechanisms, immune-modulating characteristics, and a relatively low propensity for resistance development compared to conventional antibiotics. However, more clinical trials and improvements to their formulation are needed to translate promising in vitro results into reliable patient outcomes.