Genetic Engineering of Bacteriophages Against Infectious Diseases

Abstract

Bacteriophages (phages) are the most abundant and widely distributed organisms on Earth, constituting a virtually unlimited resource to explore the development of biomedical therapies. The therapeutic use of phages to treat bacterial infections (“phage therapy”) was conceived by Felix d’Herelle nearly a century ago. However, its power has been realized only recently, largely due to the emergence of multi-antibiotic resistant bacterial pathogens. Progress in technologies, such as high-throughput sequencing, genome editing, and synthetic biology, further opened doors to explore this vast treasure trove. Here, we review some of the emerging themes on the use of phages against infectious diseases. In addition to phage therapy, phages have also been developed as vaccine platforms to deliver antigens as part of virus-like nanoparticles that can stimulate immune responses and prevent pathogen infections. Phage engineering promises to generate phage variants with unique properties for prophylactic and therapeutic applications. These approaches have created momentum to accelerate basic as well as translational phage research and potential development of therapeutics in the near future.

Diversity and Function of Phage Encoded Depolymerases

“…Due to the enormous progress in DNA sequencing technologies and recent developments in synthetic biology, engineering of bacteriophage genomes becomes a promising and powerful approach to optimize phage-based applications. For further reading recent review articles provide more detailed information on this matter (Chen et al, 2019a;Kilcher and Loessner, 2019).…”

Bacteriophage Therapy: Developments and Directions

“…The general approaches for phage therapy that have been employed include (a) fixed mixes (or cocktails) of multiple phage components (prét-à-porter, off-the-shelf), (b) cocktails of phages that are periodically modified to add activity against additional circulating clones of the target bacterium or bacteria (modifiable), (c) personalized phage therapy (phage bank, precision, sur-mesure), and (d) in vitro adapted and genetically engineered phage therapeutics [28,[34][35][36].…”

“…The fixed phage cocktail approach consists of formulating a set combination of phages to address the diversity within a single bacterial pathogen or multiple bacterial pathogens. This approach is employed to develop a phage preparation as an off-the-shelf antibacterial that can be used for treatment and/or prophylaxis [34][35][36][37]. This approach is currently being pursued commercially in Western Europe and the United States because it is most compatible with existing regulatory paths for the clinical development of antimicrobials.…”

“…The laboratory adaptation and genetic engineering of phages for therapeutic purposes is likely to be a significant force that will transform phage therapy [13,36,45,46], and the latter is already a commercial focus in the United States for companies such as Locus Biosciences and Armata Pharmaceuticals. In vitro evolution (or phage adaptation, phage training) to expand or optimize host range is an approach to modify and improve phages that has been used extensively in former Soviet countries and Eastern Europe, and was recently described in the Western literature [37,[47][48][49].…”

Bacteriophage biocontrol to fight Listeria outbreaks in seafood

“…A major hurdle in the use of bacteriophages for biocontrol is their high host specificity, being almost impossible to target all the strains within a species with a single bacteriophage (Chen et al, 2019). Therefore, the application of multiple bacteriophages within a cocktail compared to a single bacteriophage preparation may be superior, not only in reducing the risk of emerging resistant bacteria, but also in terms of providing broader coverage of the target pathogen.…”