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

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.

Engineering the Modular Receptor-Binding Proteins ofKlebsiellaPhages Switches Their Capsule Serotype Specificity

“…The modular build-up of phage RBP structures with recyclable building blocks responsible for the structural organization and receptor specificity, driven by intense horizontal transfers, provides an evolutionary highway for the rapid adaptation to the high diversity of K. pneumoniae capsules not necessarily constrained by taxonomic borders or different RBP architectures. With the recent maturation of synthetic biology tools for phage design (43)(44)(45)(46)(47)(48)(49), an increasing number of engineered phages can be constructed to gain further meaningful insights in the host recognition system by Klebsiella phage RBPs and the role of their domains in specificity and structural organization.…”

Tailored Antibacterials and Innovative Laboratories for Phage (Φ) Research: Personalized Infectious Disease Medicine for the Most Vulnerable At-Risk Patients

“…For great reviews on this topic, see Refs. [40][41][42] At the moment, TAILFR has not generated a phage of this type, but it is one of the several ways that such research may progress as more and more enhanced features are discovered. In this case, it is expected that one or more core phages will serve as the backdrop to add the enhanced component, followed by testing to determine that no other properties of the phages have been altered.…”

The Future of Phage: Ethical Challenges of Using Phage Therapy to Treat Bacterial Infections

“…Clostridium difficile is an opportunistic pathogen that multiplies rapidly when competing bacteria are eliminated by a patient’s use of antibiotics. The consequences of c. diff can include long-term damage to digestion and gut health ( Brown et al , 2017 ).…”