Phage Therapy: Engineering Viruses to Fight Bacterial Pathogens

 

Bacteriophages are viruses that infect bacterial cells, they were discovered by William Twort in 1915,  and in 1917 Felix d’Herrelle realized that they could kill bacteria. Bacteriophages require bacterias to reproduce, hence destroying the host bacterial cells. The phages are 50-200 nm in size that carry genes required for rapid and efficient replication and can infect only specific genus of bacteria. They can either have a narrow or broad host range, which determines the possibilities of therapy through phages. The majority of the phages are classified in the order of Caudovirales.

The phages are present everywhere in the environment in large amounts. They can be visualized by electron microscope, despite being small. The phages are of three types depending on the types of tails, siphoviridae, myoviridae, and podoviridae. They are also classified into lytic pages, which cause lysis of the bacterial cell or temperate phages or lysogenic phages, integrate its genome into the chromosome of host bacteria as a prophage, and influence the bacterial characteristics. 

The phage therapy was first implemented on a person suffering from an infection caused by Acinetobacter baumannii was critical, he was administered with a cocktail of phages which proved to be effective. Engineered phage therapy was later found when a woman with cystic fibrosis had a Mycobacterium sp., which was resistant to all antibiotics, but after the administration of three modified lytic phages, the woman survived the infection. 

Just like antibiotics the living antibiotics(the phages) also require to be tested and currently there are around 30 registered clinical trials around the world for treating infections caused by pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli by using appropriate phages, like T4 phages. 

It is necessary for one to understand that the phages must kill all the pathogenic bacteria, they should not produce endotoxins or not have a harmful genome that might affect the host, and the conditions in the laboratory are different from that inside the human body hence they should be stable. They can be administered intravenously, or a nebulizer is used for pulmonary infections. They can also be applied topically on infected joints. They must be stored in a temperature of below 4℃ for them to remain in a viable condition.

The phages sometimes cannot attack the pathogen with the same genus but different species as they are not specific. Manipulating phages is not logistically possible and it is very expensive, hence choosing a broad host range phages can help dealing with pathogenic bacteria or a cocktail of phages could help overcome the resistance against phages and overcome this issue.

Applying phages topically or injecting them for a short duration does not lead to any immune actions, but injecting them intravenously for a longer duration of time does. Hence the cocktail of phages must not be administered together rather slowly one by one to determine if the patient’s immune system is reacting. In some cases, immunosuppressants like rituximab can be given along with the phages.

Lytic phages are preferred than lysogenic phages since they kill the bacterial cells rather than creating prophage and increasing risk as the bacteria genome can be left. The temperate phages can be used if it has been genetically modified by BRED (Bacteriophage Recombineering of Electroporated DNA) or CRISPY-BRED (combination of BRED and CRISPR) or  CRISPY-BRIP (bacteriophage recombineering with infectious particles). It is necessary to know about the whole genome sequence of a phage as it determines if it is a suitable and specific phage, it helps in the determination of DNA packaging, if they contain genes that encode toxins, and suggests the low-risk combination of phages.

Phage therapy is often administered along with antibiotics, so that they can potentially influence each other's effectiveness through synergistic, antagonistic, or additive interactions in clinical trials to improve treatments. Resistance to phages have also been observed in clinical settings. Strategies such as isolating phages that rely on bacterial drug export pumps for infection can potentially mitigate resistance issues by exploiting trade-offs between phage susceptibility and antibiotic responsiveness in bacterial populations. The regulatory approval for clinical trials on phage therapy depends on the country.  

REFERENCE

Hatfull GF, Dedrick RM, Schooley RT. Phage therapy for antibiotic-resistant bacterial infections.

Annual Review of Medicine. 2022 Jan 27;73(1):197-211.

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