Phage engineering: how advances in molecular biology and synthetic biology are being utilized to enhance the therapeutic potential of bacteriophages

doi:10.1007/s40484-017-0094-5

Quant. Biol.

2017, Vol. 5

Issue (1) : 42-54 https://doi.org/10.1007/s40484-017-0094-5

REVIEW

Phage engineering: how advances in molecular biology and synthetic biology are being utilized to enhance the therapeutic potential of bacteriophages

Russell Brown^1,²,Andreas Lengeling³,Baojun Wang^1,²(

)

¹. School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3FF, UK
². Centre for Synthetic and Systems Biology, University of Edinburgh, Edinburgh, EH9 3FF, UK
³. Infection and Immunity Division, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK

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Abstract

Background: The therapeutic potential of bacteriophages has been debated since their first isolation and characterisation in the early 20^th century. However, a lack of consistency in application and observed efficacy during their early use meant that upon the discovery of antibiotic compounds research in the field of phage therapy quickly slowed. The rise of antibiotic resistance in bacteria and improvements in our abilities to modify and manipulate DNA, especially in the context of small viral genomes, has led to a recent resurgence of interest in utilising phage as antimicrobial therapeutics.

Results: In this article a number of results from the literature that have aimed to address key issues regarding the utility and efficacy of phage as antimicrobial therapeutics utilising molecular biology and synthetic biology approaches will be introduced and discussed, giving a general view of the recent progress in the field.

Conclusions: Advances in molecular biology and synthetic biology have enabled rapid progress in the field of phage engineering, with this article highlighting a number of promising strategies developed to optimise phages for the treatment of bacterial disease. Whilst many of the same issues that have historically limited the use of phages as therapeutics still exist, these modifications, or combinations thereof, may form a basis upon which future advances can be built. A focus on rigorous in vivo testing and investment in clinical trials for promising candidate phages may be required for the field to truly mature, but there is renewed hope that the potential benefits of phage therapy may finally be realised.

Author Summary A bacteriophage (phage) is a virus that infects and replicates within bacteria, often leading to bacterial lysis and death. Phages that are able to efficiently kill specific bacterial pathogens have long been identified as having therapeutic potential in the context of treating bacterial disease in animals and humans; however the efficacies of phage therapies have rarely reached those of antibiotic drugs. This article aims to summarise recent developments in the field of phage engineering, where the tools of molecular biology and synthetic biology are being used to modify phages in ways that enhance or alter their natural antimicrobial function.

Keywords bacteriophage phage therapy phage engineering synthetic biology

PACS:

Fund:

Corresponding Author(s): Baojun Wang

Issue Date: 22 March 2017

Cite this article:

Russell Brown,Andreas Lengeling,Baojun Wang. Phage engineering: how advances in molecular biology and synthetic biology are being utilized to enhance the therapeutic potential of bacteriophages[J]. Quant. Biol., 2017, 5(1): 42-54.

URL:

https://academic.hep.com.cn/qb/EN/10.1007/s40484-017-0094-5
https://academic.hep.com.cn/qb/EN/Y2017/V5/I1/42

Fig.1 Schematics showing three representative methods used to generate or engineer a population of phages with altered or broadened host-range.

The traditional approach to expanding treatment specificity involves isolating a number of wild-type phages with broadly similar lytic properties but with different host-specificities. When these phage are mixed and applied to a bacterial population the diversity of available host-ranges allows for the concurrent targeting of a number of different bacterial species.

A second approach involves using genome engineering to swap tail fiber genes between two phage. Generally this approach will involve swapping tail fibers from a broadly infectious but poorly lytic (or lysogenic) phage into the genome of a highly lytic phage. By doing this, it is hoped that broad-infectivity is transferred to the engineered phage through exchanged tail fibers whilst retaining the lytic properties of the wild-type phage, thus expanding the host-range.

The third approach involves randomly altering the tail fiber genes of a phage to generate a library of variants. Here, polymerase chain reaction (PCR) mutagenesis is used to amplify a pool of tail fiber variants from the wild-type genome. This gene library can then be subsequently transferred into the wild-type phage genome by homologous recombination. It is then possible to rescue a library of phages with different tail fiber mutations that can then be screened for the ability to infect a mixed population of bacteria, or for the ability to infect a specific host that could not be infected by the wild-type phage.

Fig.2 Schematics showing the two methods for phagemid packaging into infectious phage particles.

In (A) helper plasmid is co-transformed into the phage production cell along with the phagemid. This helper plasmid is capable of expressing all essential genes necessary for phage assembly, replication of the phagemid into a form that can be packaged into the phage capsid, and exit of progeny phages from the host. Therefore upon co-transformation the production cell is capable of [often inducible] production of progeny phages packaged with the phagemid ready for purification and subsequent infections.

In (B) the phage production cell is first lysogenised with a lysogenic phage. This lysogen can subsequently be transformed with the phagemid construct, and contains the entire phage genome. Upon induction of lysis, the lysogen will begin to express these genes, and concurrently amplify and package both the lysogen DNA and the phagemid into progeny phage. This mixed population of lysogenic and phagemid-packaged progeny phages will be released upon completion of lysis, and can subsequently be purified and used in subsequent infections.

Fig.3 Schematics summarizing methods for modification of the host genome and engineering altered bacterial sensitivity used for onwards treatment after infection with a genetically engineered phage.

Genes can be introduced to infected bacteria in the form of a modified lysogen or a phagemid vector. Expression of genes from these sources can either be used to directly kill bacteria, for example by using conditional lethality genes from toxin-antitoxin systems, or to sensitise the bacteria to onwards treatment such as with dominant sensitive genes.

A second option is to introduce a gene editing system such as CRISPR-Cas9, where upon phagemid or lysogen entry, genetic markers can be specifically targeted and thereby inactivated. This allows for the killing or modification of bacteria in a sequence-dependent manner, minimising the risks of disruption in non-targeted commensal bacterial populations.

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