Chirag Choudhary, Unionville High School, West Chester, Pennsylvania, USA
The idea of using a virus to kill bacteria may seem counterintuitive, but it may be the future of treating bacterial infections. Before the COVID-19 pandemic, one of the most frightening biological agents were so-called “superbugs” – antibiotic resistant bacteria – which could not be treated with conventional therapeutics. When antibiotics were first developed, they were hailed as a panacea. A panacea they were not.
The overuse and misuse of antibiotics often meant that subpopulations of bacteria would develop resistance, surviving to reproduce and skew the gene pool in favor of resistance as Charles Darwin’s theory of Natural Selection would predict. Over time, these antibiotic resistant bacteria have become much more common and are now a serious public health crisis. In fact, models show that antibiotic resistance will cost 10 million lives each year by 2050 (Sudgen, Kelly, and Davies, 2016).
Figure 1. Global prevalence of antibiotic resistance as a percentage of cases (World Health Organization, 2012).
Considering the increasing rate of resistance, designing new antibiotics to address antibiotic resistance has and will be a futile effort (World Health Organization, 2020). The rate of antibiotic resistance is simply outpacing the development of new pharmaceuticals, and it is not particularly close.
Clearly, we need to find a better way to solve our antibiotic resistance problem.
Arguably the most promising opportunity to address antibiotic resistance involves viruses. These viruses, which are known as bacteriophages (or phages), are the most common biological entities in the world, and their purpose is to infect and kill bacteria (Hungaro et al., 2014).
The idea of using phages is by no means new. In fact, phage therapy has been used in former Soviet States such as Georgia, Poland, and Russia since the 1920s (Salmond and Fineran, 2015). More recently, the Western world has started to catch up with the Eastern European antibiotic technologies; phage therapy has already been approved by the FDA for the purpose of decontaminating foods like meats and vegetables (Mooye, Woolston, Sulakvelidze, 2018).
There are a number of reasons why bacteriophages appear to be poised to replace conventional antibiotics. For one, phages are extremely accurate. Unlike antibiotics, bacteriophages only target one or a very specific group of bacterial hosts. While conventional antibiotics can indiscriminately wipe out an entire microbiome, phages can be used to selectively kill pathogens while leaving the microbiome largely unaffected. Additionally, because phages are just small clusters of proteins and nucleic acids, they are inherently nontoxic, a welcome change from the toxicities that many antibiotics come with (Loc-Carrillo and Abedon, 2011).
The place where bacteriophages really distinguish themselves is their biological nature. Although they are viruses and not technically living beings, phages come with many of the benefits that only biological organisms have. Notably, phages can be genetically reengineered (Chen et al., 2019). Because there are so many different strains and many unique strains of bacteriophage, it is nearly impossible to isolate every single strain of phage. Instead, being able to modify phage genomes to infect different hosts allows for crucial control of their activity.
There remains one elephant in the room when it comes to phage therapy: resistance. In order to be considered an effective long-term solution to the problem of antibiotic resistance, bacteriophages should not have issues with bacterial resistance. Initially, this may seem like a major sticking point because phage resistance is a very well documented phenomenon (Oechslin, 2018). The issue of phage resistance should not be particularly surprising. Due to the law of large numbers and the relatively high error rate in genetic replication, there is always going to be a small number of bacteria which have a certain mutation which confers resistance to a given strain of phage. When exposed to phages, these bacteria will be selected for and reproduce, creating more resistant bacteria. Any therapeutic developed, at least by current development strategies, will encounter this issue.
Figure 2. Eight major mechanisms of phage resistance in bacterial hosts (Azam and Tanji, 2019).
However, even in this situation, phages have an answer. Although phage resistance exists, it is not a concerning occurrence. Because phages are biological entities and rely on their bacterial hosts to copy their genetic material and reproduce, they also have very high rates of mutation. The law of large numbers works in this case as well. There are always several phages that can infect bacteria even after they mutate. This coevolution is the reason that phages and bacteria have been able to coexist for billions of years and is one of the most notable and unique qualities of bacteriophages (Oechslin, 2018).
There are still many questions that need to be addressed before phage therapy could be considered as a serious option in a clinical setting such as dosage or immune interactions, just to name a few. Although it may not happen any time soon, phage therapy could very well become the new way to cure bacterial infections.
References
Moye, Z., Woolston J., & Sulakvelidze, A. (2018, April 19). Bacteriophage applications for food production and processing. Retrieved April 12, 2021, from https://pubmed.ncbi.nlm.nih.gov/29671810/
Azam, Aa & Tanji, Yasunori. (2019). Bacteriophage-host arm race: an update on the mechanism of phage resistance in bacteria and revenge of the phage with the perspective for phage therapy. Applied Microbiology and Biotechnology. 103. 2121-2131. 10.1007/s00253-019-09629-x.
Chen, Y., Batra, H., Dong, J., Chen, C., Rao, V., & Tao, P. (2019, April 15). Genetic engineering of bacteriophages against infectious diseases. Retrieved April 12, 2021, from https://www.frontiersin.org/articles/10.3389/fmicb.2019.00954/full
Hungaro, H., Lopez, M., Albino, L., & Mendonça, R. (2014, March 18). Bacteriophage: The viruses infecting bacteria and their multiple applications. Retrieved April 12, 2021, from https://www.sciencedirect.com/science/article/pii/B9780124095489090394
Lack of new antibiotics threatens global efforts to contain drug-resistant infections. (2020, January 17). Retrieved April 11, 2021, from https://www.who.int/news/item/17-01-2020-lack-of-new-antibiotics-threatens-global-efforts-to-contain-drug-resistant-infections
Loc-Carrillo, C., & Abedon, S. T. (2011). Pros and cons of phage therapy. Bacteriophage, 1(2), 111–114. https://doi.org/10.4161/bact.1.2.14590
Oechslin F. (2018). Resistance Development to Bacteriophages Occurring during Bacteriophage Therapy. Viruses, 10(7), 351. https://doi.org/10.3390/v10070351
Salmond, G., & Fineran, P. (2015, November 09). A century of the phage: Past, present and future. Retrieved April 12, 2021, from https://www.nature.com/articles/nrmicro3564
Sugden, R., Kelly, R., & Davies, S. (2016). Combatting antimicrobial resistance globally. Nature microbiology, 1(10), 16187. https://doi.org/10.1038/nmicrobiol.2016.187
Article Thumbnail: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Phage.jpg)
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