Will phage therapy be a mainstream antibacterial tool in future? If so, what are the approaches to make them practical?

Dr. Jean-Paul Pirnay

Senior Researcher, Queen Astrid Military Hospital in Brussels

Synopsis

In an article titled “Phage Therapy in the Year 2035” in Frontiers in Microbiology under Advances in Phage Therapy: Present Challenges and Future Perspectives by Dr. Jean-Paul Pirnay enlightens a hypothesis and theory article on the path forward that is required to make the bacteriophages as a personalized treatment option for the multidrug-resistant infections. In this piece, he explains the peculiarities and inadequacies of the phages in today’s context. Further, he illuminates the two approaches (one-size fits all and personalized concept) briefly along with the synthetic biology approach to reduce phage resistance. He concludes by envisioning the phage supply chain management that includes various stakeholders, artificial intelligence, bacteriophages, and distributed ledger technology requiring community effort to make it authentic.

Why is phage therapy needed?

  • The leading peril of both community and hospital-acquired multi-drug resistant bacteria infections is emerging globally.
  • Most of the clinically pathogenic bacteria have developed resistance to almost all the available antibiotics making them pan drug-resistant.
  • Bacteriophages, the rivals of bacteria are a potential therapeutics to combat the multi-drug resistant pathogens are ubiquitous and the most abundant species on the earth.
  • Complying with lytic phages is essential for successful phage therapy.
  • Since the co-discovery of the bacteriophages by Frederick Twort, and Felix d’Hérelle in 1915 and 1917 and later George Eliava devoted his research by establishing Eliava Institute in Tbilisi, Georgia in 1923, extensive phage therapy research was in progress but camouflaged universally.
  • The encumbrance of resistant infections has reintroduced the interest in phage therapy.

A narrative fiction

  • An ambiguous backdrop in the futuristic world in the year 2035, a retired microbiologist Dr. John Iverian is stung by a bug (Halyomorpha halys).
  • He did not treat the wound, but the next morning, it turns into a necrotic would with infection as predicted by the home management system (Osuri).
  • With concern, he initiated the Phage-BEAM device (Bedside Energized Anti-Microbial) by gently removing the sterile cotton swab by gently swabbing the wound and inserted into the “sampling” area which extracts the total DNA and determines the complete metagenome data.
  • The sequenced data is sent to the “Phage XChange” server (AI-driven algorithm) predicts the phage that will lyse the infecting bacteria (identified in the metagenome) with a minimum immune reaction in the patient.
  • Osuri predicted the bacterial strain to be Streptococcus pyogenes strain FE-2033 (imminent threat to public health).
  • The device will be able to synthesize the ready-to-use therapeutic phage product in one hour, and phage suspension was prepared in the form of a hydrogel-based wound dressing containing synergistic antibiotics.
  • He applied for once a day for the next seven days, and the wound was almost completely healed without leaving his home.

Peculiarities of bacteriophages

The bacteriophages exhibit quite a few unique properties, they are;

  1. Specific to the bacteria they infect.
  2. Spare the beneficial bacteria.
  3. Phages multiply only in the presence of the host.
  4. Both bacteria and phages work mutually where they involve in selective effect resulting in “antagonistic coevolution”.

Dualistic Approaches in phage therapy

One-size-fits-all is an approach that contains broad-spectrum phage cocktails active against Gram-positive and Gram-negative bacteria commonly stumbled upon, causing various infectious diseases. This is one of the difficult methods to develop as it contained a large number of phages. An example of this approach was the PhagoBurn trail; its success was due to the prior recognized susceptible bacteria. With progressing treatment and identifying phage resistance, new phages must be supplemented to the cocktail.

The personalized concept is the one in which one or more phages are selected from a phage bank or previously characterized backgrounds. It is more sustainable with less selection pressure contributing to the phage resistance. However, logistical constraints and licensing paths remain a limitation.

Synthetic biology

Synthetic biology approaches such as yeast-based platforms, cell-free transcription-translation (TXTL) systems, and genetic engineering strategies must be developed to satisfy the precision and personalized phage therapy. Links between bacterial genomes and infecting phage genomes must be established using the Deep Learning process. The shortcomings are a massive amount of data linking the lytic phage genomes to the host must be generated that is currently unavailable. The researchers and institutes are not profound to submit their data to a single centralized database. The absence of quick, reliable, and cheap synthesis of large DNA molecules are a few constraints that need to be taken care of. The de novo synthesis of phage genomes requires assembling several genome fragments using yeast artificial chromosomes, cell-free phage production systems, or chemical assembly.

Concluding remarks

  • With the use of synthetic phages, there is no need for the maintenance of phage banks or the transfer of bacterial isolates throughout the world for the phage search.
  • It would be easy to combat epidemic outbreaks and bioterrorism.
  • Lethal strains requiring higher biosafety conditions can be cultured in safe and less feasible environments.
  • The negative impact, such as endotoxins on patients, could be minimized or evaded.

Take-home message

  • The emerging studies on the efficacy of bacteriophages in treating the multi-drug resistant infection prove them to be an alternative to antibiotics.
  • To make the treatment from bench to bedside, several strategies have to be worked out to accomplish practicability.
  • Aspects of phage and bacterial receptor interaction, artificial intelligence, distributed ledger technologies, genome data on bacteria and phages, stakeholders (Sponsors, community, researchers, patients), and phage synthetic techniques have to be constituted to make this therapy a reality to every patient.

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