Sam Jarada
Glossary
bactericidal, bacteriostatic, capsid, cell wall, DNA gyrase, dosage, dysentery, efficacy, enzyme, microbiome, lipid, lysis, lytic, nucleic acid, pathogenic, placebo, RNA, transcription, translation
Introduction
Phage therapy is a type of treatment that makes use of bacteriophages (phages), (a type of virus that only infect bacteria). Phages are composed of a nucleic acid, which can be either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), contained within a capsid head, which is made up of protein. Bacteriophages have tail fibres that allow them to move. They also have a spike that they use to adhere to bacterial cells.
There are many distinct types of bacteriophages. Each type targets only a specific type of bacteria. Phages are one of the most diverse and ubiquitous microorganisms on the planet, inhabiting all ecosystems. It is likely that there are far more types of bacteriophages than types of bacteria [1].
As phages only attack bacteria, scientists have been researching the possibility of using phages to treat bacterial infections, in a practice known as phage therapy. This post will explore what phage therapy is, the main applications of phage therapy, current research into phage therapy, the effectiveness of phage therapy in comparison to antibiotic treatment, the advantages and disadvantages of phage therapy compared to antibiotic treatment, and ethical concerns relating to phage therapy. We will also consider whether phage therapy is likely to be considered a standard treatment option for the treatment of bacterial infections in future.
What is phage therapy?
For as long as humans have existed on earth, they have been infected by a variety of microorganisms, including viruses, bacteria, and fungi. The standard treatment for bacterial infections is using penicillin (antibiotic treatment) which was discovered in 1928. However, in recent times, it is becoming increasingly challenging to treat certain bacterial infections due to the development of antibiotic resistance. Antibiotic resistance arises as a result of the accumulation of particular types of mutations in the genomes of certain bacterial strains. These mutations make these strains resistant to one or more of the currently used antibiotics in standard antibiotic treatment.
Antibiotic resistance has led to the emergence of superbugs that are resistant to one or more of the antibiotics currently used for the standard treatment of bacterial infections. One of these superbugs is Methicillin-resistant Staphylococcus aureus (MRSA), a bacterium that is resistant to multiple antibiotics. To address antibiotic resistance, scientists advise physicians to be conservative in prescribing antibiotics and to inform patients that antibiotics are not adequate for treating viral infections [2]. However, another approach to addressing antibiotic resistance and treating bacterial infections is considering the broader use of phage therapy.
Phage therapy uses bacterial viruses or bacteriophages to treat bacterial infections. It has been used by healthcare professionals for around a century. However, western medicine is currently debating the use of natural bacteriophages to treat bacterial infections [3].
What are the main applications of phage therapy?
Although phage therapy is not a standard treatment option for treating bacterial infections, there is potential for using it to routinely treat such conditions, especially for cases that do not respond to antibiotic treatment. A study of 550 patients suffering from a range of bacterial infections, who were treated with phage therapy, was conducted between 1981 and 1986. This study demonstrated that the therapy was effective in 508 patients (92.3%) in whom antibiotic treatment was ineffective [4].
Another study was conducted in Tbilisi, Georgia, between 1963 and 1964 and included over 30,000 children between the ages of 6 months and 7 years who had bacterial dysentery. The researchers divided the participants into two groups, with one group receiving Shigella phages orally, once per week. The other group was not treated with phages and received only a placebo [5].
While substantial data supports the use of phage therapy, it is still not currently approved by the US FDA (Food and Drug Administration) as an alternative treatment option for bacterial infections and is only used in emergency or experimental situations.
Current research into phage therapy
Although the FDA has not approved phage therapy as a treatment option for bacterial infections, they did support the first bacteriophage trial in which physician researchers at the University of California San Diego (UCSD) collaborated with a biotechnology company in San Diego called Ampliphil Biosciences Cooperation. The clinical trial included just ten patients. The trial was allowed to be conducted on a psychiatry professor by the name of Tom Patterson, PhD got the treatment from a healthcare facility to treat an antibiotic resistant bacterium called Acinetobacter baumannii, indicating that phage therapy was a last resort and ever since this happened, patients are starting to approve the use of phage therapy [6].
Belgium is exploring the use of phage therapy for superbug infections in more than one hundred patients due to changes in health regulations in 2019 to allow more experiments; this means that phage therapy will become more common in Belgian healthcare, and with these patients, phage therapy was used after antibiotics failed. For example, in March 2016, a 30-year-old woman injured in a major incident was treated with antibiotics after her wounds became infected with Klebsiella pneumonia [7]. The particular strain that the patient was infected with was foudn to be resistant to standard antibiotics. A doctor by the name of Anais Eskenazi decided to consider phage therapy for this particular case. After two years of attempting to treat the infections with a range of antibiotics, phage therapy was given in parallel with antibiotics and this combined treatment was effective in clearing the infection.
These two instances show that phage therapy can be an effective treatment, with several companies working on developing bacteriophage therapies. One of these is Fixed Phage Ltd. (based in Glasgow), which researches the applications of bacteriophages. The Bacteriophage Therapy Summit gathers researchers working on both phage therapy and antibiotic therapies annually.
How does phage therapy work as opposed to antibiotics?
The bacteriophage lifecycle involves a series of phases. Firstly, a bacteriophage attaches to the bacterial cell in the adsorption phase. This is a specific stage because each bacteriophage type usually targets a kind of bacteria. For example, the Escherichia virus T4 infects Escherichia coli bacteria (E. coli). The bacteriophage injects its genetic material into the bacterium.
The virus then undergoes replication by hijacking the machinery of the cell and making use of certain bacterial enzymes. It utilizes bacterial enzymes to create proteins and lipids required to make viral capsids. At the DNA replication stage, the DNA or genetic material of bacteriophages is copied multiple times. In transcription and translation, some of the DNA replicated is converted into RNA, which gets converted into proteins used to build more bacteriophages.
In the phage assembly stage, all of the DNA that is not transcribed and translated into protein alongside the translated proteins and lipids are used to build more bacteriophages. Once the bacteriophages are created, they burst out of the bacterial cell in host cell lysis. The cycle repeats until all the bacteria are destroyed [8]
Although antibiotics have various effects on different bacteria, their effectiveness can be reduced against bacteria when healthcare professionals overprescribe them to patients or when farmers feed antibiotics to livestock to protect them from bacterial infections.
How do the advantages and disadvantages of phage therapy compare to antibiotics?
One advantage of phage therapy is that the bacteriophages are bactericidal (have the ability to kill bacteria) in nature. Therefore, bacteria that are infected with these viruses cannot survive. In contrast, certain antibiotics like tetracycline are bacteriostatic, meaning there is a chance that bacteria can overcome the effects of tetracycline by developing resistance against it. The bacteria evolve as a result.
Another advantage of phage therapy is that it does not disrupt gut microbiome. This is because bacteriophages are specific in the bacteria that they target. Hence, it has minimal impact on the gut environment. On the other hand, antibiotics tend to generalize which bacteria it targets. A problem caused by this is that these drugs can attack and kill all bacteria, even the useful ones, thus potentially destroying the flora.
A disadvantage of phage therapy is that not all bacteriophages are good therapeutic agents. To be effective, therapeutic phages must have a high chance of confronting and killing pathogenic bacteria while at the same time having a low probability of negatively impacting the inner body’s environment. These features can be guaranteed if phages are lytic, stable under tightly controlled conditions, and able to go through suitable efficacy and safety studies.
A further disadvantage of phage therapy is that as it specifically targets only a particular species of bacteria. For example, if an individual is infected with both E. coli and Streptococcus (two completely different species of bacteria), using phage therapy against one of these baceria can result in the other bacterial species gaining an advantage due to reduced competition for nutrients and space. To resolve this, it is necessary to use a ´cocktail´of different types of phages and/or to combine phage therapy with other types of treatment [10].
Antibiotics have several properties that make them suitable for treating bacterial infections. They are generally effective against infections caused by “living” microorganisms and can kill bacteria in the body or inhibit bacterial growth. Additionally, they do not harm human bodily cells since the chemicals in antibiotics are designed to attack specific bacteria and are usually considered safe for all age groups and pregnant women. Some antibiotics are being developed to tackle cancerous cells in the body so they can be used to cure cancer.
However, a possible side effect of antibiotic therapy is diarrhea which results due to the disruption to the gut microbiome which in turn causes a depletion of beneficial bacteria that would normally help to eliminate pathogenic bacteria. The overuse of antibiotics to treat livestock in the meat industry can lead to these antibiotics being ingested by human which can increase the likelihood of certain bacterial strains developing resistance to these antibiotics [11].
Ethical concerns
Although phage therapy appears to have potential benefits, there are still a few issues that need to be considered. One prominent issue is that of patient consent. If phage therapy were to be approved in countries that have not yet authorized its use, it would be necessary to obtain patient consent before administering these active viruses.
The main challenge with developing phage therapy is isolating phages that are specific to the type of bacterial infection that is to be treated. For phage therapy to be successful, diseases must be diagnosed precisely and correctly, the precise type of phage must be selected and cultured, and the treatment must be performed in such a way as to avoid negatively impacting the patient’s immune system. The tailored approach used to developing this type of treatment is a unique example of precision medicine.
Patient consent is one of the foundational pillars of medical ethics. Patients can refuse to receive a treatment for varied reasons. One reason can be that the patients do not adequately understand the biological and medical basis of the treatment and the risks associated with it.
Furthermore, many practicing physicians may not be knowledgeable regarding bacteriophages as research into phages is still in the preliminary stages. Therefore, to obtain patient consent, both patients and physicians would need to be educated on the subject of phage therapy and it will be necessary to clearly inform patients of the known and unknown risks relating to this treatment option [12].
Will phage therapy be considered a treatment option?
Based on the data that has been published on phage therapy to date, it is likely that doctors may eventually use phage therapy as a standard treatment option against bacterial infections in the future. However, to reach this stage, it will be necessary to conduct a thorough analysis of past research into bacteriophages and continue to carry out further research into the risks and benefits of phage therapy. It is likely that as time goes on, the problem of antibiotic resistance will only worsen as antibiotics continue to be misused or overused worldwide.
While modern medicine has generated a wide range of innovative technologies to tackle many diseases inflicted by pathogenic agents such as bacteria, it may be necessary to develop substitute or alternative treatment options in future if humanity is to win the battle against newly emerging pathogens and strains of microorganisms that are resistant to our current standard treatments.
In the case of phage therapy, it will be essential to conduct rigorous clinical trials to test the dosage, safety, and efficacy of bacteriophages on patients that are infected with superbugs such as MRSA, to definitively assess whether the use of phages has the potential to become a standard treatment option for bacterial infections that do not respond to antibiotic treatment.
Useful links
The Deadliest Being on Planet Earth – The Bacteriophage: https://www.youtube.com/watch?v=YI3tsmFsrOg&t=26s
How antibiotics work: https://www.youtube.com/watch?v=X1GT2bKgci8
What causes antibiotic resistance? – Kevin Wu: https://www.youtube.com/watch?v=znnp-Ivj2ek
How can we solve the antibiotic resistance crisis? – Gerry Wright: https://www.youtube.com/watch?v=ZvhFeGEDFC8
Why is the gut microbiome important? – Microbiology Society: https://www.youtube.com/watch?v=AsyzqhFKLoI
Fixed phage limited, a biotechnology company using bacteriophages to solve problems caused by bacteria: https://www.fixed-phage.com/
Bacteriophage Therapy Summit, an event discussing the use of phage therapy and other treatment options against bacteria: https://bacteriophage-summit.com/
References
1.The Editors of Encyclopedia Britannica. “Bacteriophage | Definition, Life Cycle, & Research.” Encyclopædia Britannica, 12 Oct. 2018, britannica.com/science/bacteriophage.
2. FDA (2019). Combating Antibiotic Resistance. [online] U.S. Food and Drug Administration. Available at: https://www.fda.gov/consumers/consumer-updates/combating-antibiotic-resistance.
3. Lin, D.M., Koskella, B. and Lin, H.C. (2017). Phage therapy: An alternative to antibiotics in the age of multi-drug resistance. World Journal of Gastrointestinal Pharmacology and Therapeutics, (3), p.162.
4. Slopek, S., Weber-Dabrowska, B., Dabrowski, M. and Kucharewicz-Krukowska, A. (1987). Results of bacteriophage treatment of suppurative bacterial infections in the years 1981-1986. Archivum immunologiae et therapiae experimentalis, [online] 35(5), pp.569–583. Available at: https://europepmc.org/article/med/3455647.
5. Sulakvelidze, A., Alavidze, Z. and Morris, J.G. (2001). Bacteriophage Therapy. Antimicrobial Agents and Chemotherapy, [online] 45(3), pp.649–659. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC90351/.
6. Voelker R. FDA Approves Bacteriophage Trial. JAMA [Internet]. 2019 Feb 19;321(7):638–8. Available from: https://jamanetwork.com/journals/jama/article-abstract/2725218
7. Le Page M. Educational access digital subscriptions | New Scientist [Internet]. institutions.newscientist.com. 2022 [cited 2022 Apr 16]. Available from: https://institutions.newscientist.com/article/2304997-phage-therapies-for-superbug-infections-are-being-tested-in-belgium/amp/
8. Brives, C. and Pourraz, J. (2020). Phage therapy as a potential solution in the fight against AMR: obstacles and possible futures. Palgrave Communications, [online] 6(1), pp.1–11. Available at: https://www.nature.com/articles/s41599-020-0478-4.
9. unknown (2018). Figure 1. Mode of action of antibiotics. Antibiotics can inhibit the… [online] ResearchGate. Available at: https://www.researchgate.net/figure/Mode-of-action-of-antibiotics-Antibiotics-can-inhibit-the-growth-of-bacteria-by_fig1_331703622.
10. Loc-Carrillo, C. and Abedon, S.T. (2011). Pros and cons of phage therapy. Bacteriophage, 1(2), pp.111–114.
11. Heba Soffar (2019). Antibiotics advantages and disadvantages | Science online. [online] Science online. Available at: https://www.online-sciences.com/health/antibiotics-advantages-and-disadvantages/.
12. Anomaly, J. (2020). The Future of Phage: Ethical Challenges of Using Phage Therapy to Treat Bacterial Infections. Public Health Ethics, 13(1).