How to Train Your Phage: The Recent Efforts in Phage Training

Anan Safwat,Salsabil Makky,Ayman El-Shibiny,Abdallah Abdelsattar,Alyaa Dawooud,Nouran Rezk,Philip Richards

doi:10.3390/biologics1020005

Anan Safwat, Salsabil Makky + Show 5 more

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https://doi.org/10.3390/biologics1020005

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Abstract

Control of pathogenic bacteria by deliberate application of predatory phages has potential as a powerful therapy against antibiotic-resistant bacteria. The key advantages of phage biocontrol over antibacterial chemotherapy are: (1) an ability to self-propagate inside host bacteria, (2) targeted predation of specific species or strains of bacteria, (3) adaptive molecular machinery to overcome resistance in target bacteria. However, realizing the potential of phage biocontrol is dependent on harnessing or adapting these responses, as many phage species switch between lytic infection cycles (resulting in lysis) and lysogenic infection cycles (resulting in genomic integration) that increase the likelihood of survival of the phage in response to external stress or host depletion. Similarly, host range will need to be optimized to make phage therapy medically viable whilst avoiding the potential for deleteriously disturbing the commensal microbiota. Phage training is a new approach to produce efficient phages by capitalizing on the evolved response of wild-type phages to bacterial resistance. Here we will review recent studies reporting successful trials of training different strains of phages to switch into lytic replication mode, overcome bacterial resistance, and increase their host range. This review will also highlight the current knowledge of phage training and future implications in phage applications and phage therapy and summarize the recent pipeline of the magistral preparation to produce a customized phage for clinical trials and medical applications.

Highlights

The emergence of antibiotic resistance in bacterial pathogens, accompanied by a rise in the attributable mortality [1], has led to considerable research effort being directed toward finding alternative treatments
This review aims to highlight the common strategies based on previously approved regulations [32,33] to optimize phage agents for biocontrol applications, including how phages can be deliberately switched between lytic and lysogenic cycles and how a better understanding of phage:bacteria interactions will subdue the development of bacterial resistance and expand phage host range
Phage biotechnology has the potential to remedy a number of challenges to sustainably and phage training will be key to developing appropriate phage interventions. Phages change their behavior based on different environmental variables; for example, phages convert their mode of action from lysogenic to lytic mode and vice versa by controlling the expression of the lytic gene cluster in response to internal or external host stress

Summary

Introduction

The emergence of antibiotic resistance in bacterial pathogens, accompanied by a rise in the attributable mortality [1], has led to considerable research effort being directed toward finding alternative treatments. Bacteriophages (phages) are viruses that infect bacteria [2], and deliberate therapeutic application of phages to infections caused by multi-drug resistant bacteria is a promising alternative to antimicrobials. Phages are characterized by a narrow host range and a typical phage particle can only infect a limited number of closely related bacterial species or strains within the same species [5]. When a phage enters the bacterial cell it begins one of two primary life cycles; virulent phages pursue the lytic life cycle where they quickly lyse their host cell and release viral particles, while temperate phages can integrate their nucleic acid into the host genome and pursue the lysogenic life cycle [6].

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