# Phages as antimicrobials against multi-drug resistant bacteria

## TL;DR

This review explores using bacteriophages and their enzymes as alternatives to antibiotics for fighting drug-resistant bacteria.

## Contribution

The paper highlights phage-derived enzymes like endolysins as promising antimicrobial tools with fewer limitations than whole phages.

## Key findings

- Whole bacteriophages show high specificity but face challenges like host range and immune response.
- Phage-derived enzymes like endolysins and depolymerases have lower resistance risks and better regulatory potential.
- 27 studies on phage enzymes showed promising results compared to 11 on whole phages.

## Abstract

Multi-drug resistant bacteria (MDR) pose a major public health challenge. Their ability to exchange resistance genes through Horizontal Gene Transfer (HGT) promotes the appearance of resistant strains, limiting antibiotic treatments for infections caused by these MDR bacteria. Among alternative approaches, phage therapy stands out as a promising strategy that utilizes bacteriophages to specifically target and effectively eliminate bacteria. This narrative review provides an overview of the current knowledge on the use of whole bacteriophages as antimicrobial agents in human and veterinary medicine, as well as in the food industry whether used alone, in cocktails, or combined with antimicrobials. While whole phages offer high specificity and an efficient elimination of bacteria, their application is associated with several limitations, including their contribution to HGT, the emergence of bacterial resistance, their narrow host range, the immune recognition, and the difficulties posed by their regulation. To address these challenges, this review focuses on phage-derived enzymatically active proteins, such as endolysins and depolymerases, as alternative antimicrobial tools, used alone or in combination. These phage components, being smaller and structurally simpler than whole phages, behave more similarly to conventional antimicrobial compounds. They have so far presented a low risk of bacterial resistance appearance and less chance of immune response. In addition, their classification as antimicrobial enzymes or conventional biologics could facilitate regulatory approval by aligning with existing regulatory frameworks. A total of 40 studies were included in this narrative review, highlighting the outcomes of applications involving whole bacteriophages (n = 11) and phage-derived enzymes, including endolysins and depolymerases (n = 27).