Hello everyone and welcome to this week's blog post, which is the second in a series about antibiotic resistance. As you will recall, in last week's blog post we discussed how various factors mean that antibiotic resistance is on the rise and antibiotics are becoming harder to produce. This week, I want to explore an alternative method of treating bacterial infections - phage therapy. According to the Phage Therapy Center, phage therapy is "the therapeutic use of lytic bacteriophages to treat pathogenic bacterial infections". In this article, I will examine what phage therapy is, how it works and compare it to antibiotics.
Bacteriophages are a type of tiny virus that can infect bacteria. They do this by attaching themselves to a receptor on the bacteria, drilling a hole through the bacterial wall and then injecting their own viral genome into the bacterial cell. This has two effects which both combat the spread of the bacterial infection.
Firstly, the bacteria stops using its own RNA/DNA to reproduce and instead just uses the viral genes, meaning that the bacteria can no longer create new bacterial proteins and thus can't replicate. Secondly, as the viral RNA/DNA is used for protein synthesis, viral proteins are created. These are assembled into more bacteriophages.
Once the entire bacterial cell is filled with bacteriophages, the bacteriophages secrete an enzyme called endolysin, which forges a hole in the bacteria's cell wall. As the pressure inside the cell is much higher than outside the cell, the contents of the cell are forced out, resulting in the bacteria cell being destroyed and the bacteriophages being released to infect more bacteria.
The idea of injecting bacteriophages into humans to cure them of bacterial infections is not a new concept. Bacteriophages were discovered in 1915 by Frederick Twort, and phage therapy research began soon after. Indeed, in 1923, Georg Eliava founded the Eliava Institute of Bacteriophages, Microbiology and Virology in Georgia, which today still plays an important role in the research of bacteriophages.
Bacteriophages have many advantages over antibiotics, most notably their specificity. A single antibiotic can attack many types of bacteria, including the good bacteria which make up your microbiome. Contrastingly, as bacteriophages attach themselves to specific receptors on specific bacteria, they are much more specific to the type of bacteria they destroy. This has two very important impacts.
Firstly, following phage therapy, your microbiome is preserved. This means that the bacteria that help you digest certain foods and absorb their nutrients are preserved. Furthermore, the microbiome also plays an important role in protecting you from other infections, so any treatment of bacterial infections which does not affect the microbiome is very beneficial. For more information about the human microbiome, read my blog post here.
Additionally, using bacteriophages also decreases the speed at which superbugs can develop. The overuse of antibiotics has resulted in many bacteria becoming resistant to several types of antibiotics. This resistance occurs when bacteria evolve to become less susceptible to antibiotics. Bacteria can also transfer resistance to other bacteria by conjugation, meaning that a bacteria may be resistant to an antibiotic without ever being exposed to it.
In stark contrast to antibiotics, bacteriophages only target specific bacteria, so resistance can't spread to different species of bacteria. Additionally, unlike antibiotics, bacteriophages can also evolve. This means that it is much harder for bacteria to develop resistance to bacteriophages, as the bacteriophages can adapt to combat the resistant bacteria. Moreover, according to a paper published in 2011, if a bacteria becomes resistant to bacteriophages, it loses its resistance to antibiotics. As a result, researchers are also looking into combining both phage therapy and antibiotics for the treatment of bacterial infections.
Bacteriophages are also more effective at destroying certain types of bacteria, especially those which have a biofilm covered by a polysaccharide layer. This is because antibiotics can not easily penetrate the biofilm, whereas bacteriophages can.
One of the major disadvantages of phage therapy is that we simply don't know enough about it to use it widely. For example, we don't know whether bacteriophages are completely harmless to humans. Additionally, some bacterial infections may be untreatable with phage therapy as the bacteria may not have any corresponding bacteriophages which attack it. While there are approximately a trillion phages for every single grain of sand in the world, we have only tested a tiny portion of them, so it is possible that there are some classes of bacteria which phage therapy may not work against.
In addition, some people worry that phages may cause an imbalance in your own immune system, causing it to attack itself. Further, as the bacteriophages need to be specific to the bacteria, treatment can only begin once the exact strain of bacteria is identified and the corresponding bacteriophage is determined. Although this could be partially overcome using a mixture of bacteriophages which each attack a different bacteria, this would drive up the cost of treatment and increase its complexity, making these bacteriophage mixtures much harder to produce
Currently, phage therapy is still in its early stages. Even though phage therapy is being used therapeutically for the treatment of bacterial infections in countries such as Georgia and Russia, it has not seen widespread use in Western countries. This is partly because of higher safety standards in the West but also because of a lack of funding. For many years, pharmaceutical companies have been reluctant to invest in the research of phage therapy, however, this is now changing. Indeed, in 2019, the first clinical trial researching phage therapy in the United States was conducted, suggesting that phage therapy may soon become more prevalent in the West.
In conclusion, phage therapy is a promising alternative for antibiotics. While more research needs to be conducted, especially in terms of working out their safety, required dosage and in matching bacteriophages to bacterial infections they can treat, current evidence seems to suggest that phage therapy will be an effective and safe form of treatment. If this research is conducted, then I contend that phage therapy will become a vital part of future medicine.
Sources:
Edgar, R., Friedman, N., Molshanski-Mor, S., & Qimron, U. (2011). Reversing Bacterial Resistance to Antibiotics by Phage-Mediated Delivery of Dominant Sensitive Genes.Applied And Environmental Microbiology,78(3), 744-751. doi: 10.1128/aem.05741-11
Stewart, P. (2002). Mechanisms of antibiotic resistance in bacterial biofilms.International Journal Of Medical Microbiology,292(2), 107-113. doi: 10.1078/1438-4221-00196
Keen, E. (2014). A century of phage research: Bacteriophages and the shaping of modern biology.Bioessays,37(1), 6-9. doi: 10.1002/bies.201400152
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