Engineered Bacteriophage Therapeutics: Rationale, Challenges and Future

Abstract

The current problems with increasing bacterial resistance to antibacterial therapies, resulting in a growing frequency of incurable bacterial infections, necessitates the acceleration of studies on antibacterials of a new generation that could offer an alternative to antibiotics or support their action. Bacteriophages (phages) can kill antibiotic-sensitive as well as antibiotic-resistant bacteria, and thus are a major subject of such studies. Their efficacy in curing bacterial infections has been demonstrated in in vivo experiments and in the clinic. Unlike antibiotics, phages have a narrow range of specificity, which makes them safe for commensal microbiota. However, targeting even only the most clinically relevant strains of pathogenic bacteria requires large collections of well characterized phages, whose specificity would cover all such strains. The environment is a rich source of diverse phages, but due to their complex relationships with bacteria and safety concerns, only some naturally occurring phages can be considered for therapeutic applications. Still, their number and diversity make a detailed characterization of all potentially promising phages virtually impossible. Moreover, no single phage combines all the features required of an ideal therapeutic agent. Additionally, the rapid acquisition of phage resistance by bacteria may make phages already approved for therapy ineffective and turn the search for environmental phages of better efficacy and new specificity into an endless race. An alternative strategy for acquiring phages with desired properties in a short time with minimal cost regarding their acquisition, characterization, and approval for therapy could be based on targeted genome modifications of phage isolates with known properties. The first example demonstrating the potential of this strategy in curing bacterial diseases resistant to traditional therapy is the recent successful treatment of a progressing disseminated Mycobacterium abscessus infection in a teenage patient with the use of an engineered phage. In this review, we briefly present current methods of phage genetic engineering, highlighting their advantages and disadvantages, and provide examples of genetically engineered phages with a modified host range, improved safety or antibacterial activity, and proven therapeutic efficacy. We also summarize novel uses of engineered phages not only for killing pathogenic bacteria, but also for in situ modification of human microbiota to attenuate symptoms of certain bacterial diseases and metabolic, immune, or mental disorders.

Interactions of Bacteriophages with Animal and Human Organisms—Safety Issues in the Light of Phage Therapy

“…Thus, an attempt has been made to create bacteriophages with modified surface proteins, which could theoretically attenuate their immunogenicity. However, effective control of the circulation of bacteriophages with modified proteins has not been confirmed [91]. Nevertheless, there are reports confirming that the pharmacokinetics of such bacteriophages has been altered, but this information is not entirely conclusive.…”

Bacterial Biofilm Destruction: A Focused Review On The Recent Use of Phage-Based Strategies With Other Antibiofilm Agents

“…Phages, in addition to their lytic potential and antibiofilm activities, can be modified to be used as delivery vehicles of cargos such as nucleic acids, nanomaterials, therapeutic drugs and diagnostic probes. 67 , 124 In such cases, temperate phages may be of interest for delivering programmable DNA nucleases associated with CRISPR to reverse antibiotic resistance and destroy plasmids that confer antibiotic resistance. 125 In this current view, phages can also be modified to deliver antibiofilm agents for biofilm destruction.…”

Tailed Lytic Bacteriophages of Soft Rot Pectobacteriaceae

“…Phages can adapt their specificity to such mutants naturally, using horizontal gene transfer, as seen for different Studiervirinae phages using almost identical TSP [135], or through the acquisition of Ackermannviridae-like TSP by phage Sucellus. Due to the unified composition of their adsorption apparatus, Podophages and Myophages are often considered as a subject for directed gene engineering, adopting them for a broader range of host bacteria [191][192][193][194]. This approach is often criticised for the addition of a "genetically modified organism" status to the complicated goal of defining bacteriophages as therapeutic drugs [192].…”