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Bacteriophages, viruses that can save lives instead of taking them

Updated: Jan 23, 2022


Antibiotics are one of the greatest scientific advances ever made. A world in which a simple bacteria infection would end up in death is now foreign to many of us due to the prevalence of antibiotics. However, the rise of antibiotic resistant bacteria has sparked fear that such a world will become reality again. Groups such as the World Health Organization have deemed antibiotic resistant bacteria a critical threat, estimating that by 2050 there will be no effective antibiotic available to treat infections if no new drugs are developed [1]. Due to the slowing pace of antibiotic development and the rapid rise of antibiotic resistance, new treatment methods are being investigated by researchers [2]. One particular treatment that has perhaps been the most talked about is phage therapy.


Phage therapy is the method of using bacteriophages, viruses that specifically infect bacteria, to treat bacterial infections [3].Their ability to infect bacteria was first observed by French scientist Félix d'Hérelle [4]. This started an initial effort of scientists to isolate bacteriophages to use against bacterial infections. However, the prevalence of antibiotics caused phage therapy to come to a standstill [5]. In recent decades, interest in phage therapy has been renewed as it possesses several properties that make it optimal to deal with antibiotic resistant bacteria. For one, phages infect bacteria through mechanisms that are different from how antibiotics work. As such, numerous studies have shown the ability of phages to inhibit multi-drug resistant (MDR) bacteria [6]. In one study, researchers were able to cure mice infected with MDR Staphylococcus aureus with the bacteriophage phage phi MR11 [7]. Similar success has been demonstrated with human patients such as the successful treatment of diabetic toe ulcers with anti staphylococcal bacteriophage Sb-1 [8]. Second, bacteriophages have been demonstrated to have little side effects [9]. Bacteriophages have high host specificity. Hence, they do not infect other cells in the organism [19]. Their only side effect is a possible immune response from both the humoral and cellular immune systems with less than severe symptoms typically. It has been hypothesized that the rapid release of bacteriophage antibodies in certain cases may lead to dangerous immune reactions such as anaphylaxis, but that has not been reported in cases of phage therapy [9]. Third, bacteriophages are vastly abundant, being perhaps the most abundant life forms on earth, and are constantly replicating and evolving. They are ubiquitous organisms found in many diverse environments such as soil, water, feces, etc [20]. Hence, it is unlikely that we would run out of bacteriophages [2].


For all the research there is in phage therapy, one may well wonder why hospitals are not using phage therapy currently. This is because there are issues to phage therapy preventing it from being used widespread. One such issue is that bacteria have developed defense mechanisms against bacteriophage infection through a variety of mechanisms including CRISPRs, restriction modification systems, and more [10]. Additionally, due to the specific host range of bacteriophages, a bacterial infection has to be analyzed and then the right bacteriophage strains selected for phage therapy, a costly effort [6]. Another issue is that the pharmacokinetics, the study of a drug's path through an organism’s body, of phage therapy is quite complicated and not well-defined [9].


Each of these issues had prevented phage therapy from becoming a reality, but now new developments in phage therapy have helped pave a path through these issues. In dealing with bacteriophage resistance, it should be noted that it is highly unlikely that there will evolve a bacteria resistant to all bacteriophages. However, as bacteriophage resistance is a concern, multiple different strategies have been proposed to deal with bacteriophage resistance such as the anti-virulence strategy, a strategy that uses a bacteriophage as a selective pressure to shift the bacterial population to one that carries fewer infectious factors, and the antibiotic-phage combination therapy, which mixeds phages and antibiotics into a cocktail [2, 12-16].


In past decades, selecting the appropriate bacteriophages from bacterial infection analysis was difficult due to technological limitations. However, modern technological capabilities make the isolation and identification of bacteriophage strains relatively straightforward. The only issue is to assemble a database of various bacteriophage strains, a process that has already begun [17]. Finally, many recent new studies into the pharmacokinetics of phage therapy have revealed important details on the dosages needed for effective treatment and new methods that can improve the pharmacokinetics of phage therapy such as nanoparticle encapsulation [21, 22].


Bacteriophage therapy has potential to save lives and deal with the antibiotic resistance bacteria problem. Its ability to attack antibiotic resistance bacteria, its few side effects, and its abundant supply has given it much attention. Although several obstacles such as phage resistance have prevented it from being applied, advances and strategies to overcome these obstacles have been made. Currently, there are several FDA clinical trials utilizing phage therapy. These include Adaptive Phage Therapeutics’ bacteriophage therapy for prosthetic joint infections, and Yale’s cystic fibrosis bacteriophage therapy [23]. In addition, numerous biotechnology companies have invested into phage therapy, and it is expected that the phage therapy market will hit its peak between 2021 and 2028 [25]. For those who desire to help partake in the battle against antibiotic resistant bacteria here at Cornell, one should look no further than Cornell's own Professor Josh Chappie, whose work has been to understand bacteria defense mechanisms against bacteriophages [18].


References:

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  3. Srisuknimit, V. (2018, February 2). Bacteriophage: A solution to our antibiotics problem? how we can us a virus to fight bacterial infection. Science in the News. Retrieved November 13, 2021, from https://sitn.hms.harvard.edu/flash/2018/bacteriophage-solution-antibiotics-problem/.

  4. Salmond, G. P. C., & Fineran, P. C. (2015). A century of the phage: Past, present and future. Nature Reviews Microbiology, 13(12), 777–786. https://doi.org/10.1038/nrmicro3564

  5. Knezevic, P., Hoyle, N. S., Matsuzaki, S., & Gorski, A. (2021). Editorial: Advances in Phage Therapy: Present Challenges and Future Perspectives. Frontiers in Microbiology, 12, 1390. https://doi.org/10.3389/fmicb.2021.701898

  6. Taati Moghadam, M., Khoshbayan, A., Chegini, Z., Farahani, I., & Shariati, A. (2020). Bacteriophages, a New Therapeutic Solution for Inhibiting Multidrug-Resistant Bacteria Causing Wound Infection: Lesson from Animal Models and Clinical Trials. Drug design, development and therapy, 14, 1867–1883. https://doi.org/10.2147/DDDT.S251171

  7. Rashel, M., Uchiyama, J., Ujihara, T., Uehara, Y., Kuramoto, S., Sugihara, S., Yagyu, K., Muraoka, A., Sugai, M., Hiramatsu, K., Honke, K., & Matsuzaki, S. (2007). Efficient elimination of multidrug-resistant Staphylococcus aureus by cloned lysin derived from bacteriophage phi MR11. The Journal of infectious diseases, 196(8), 1237–1247. https://doi.org/10.1086/521305

  8. Fish, R., Kutter, E., Wheat, G., Blasdel, B., Kutateladze, M., & Kuhl, S. (2018). Compassionate Use of Bacteriophage Therapy for Foot Ulcer Treatment as an Effective Step for Moving Toward Clinical Trials. Methods in molecular biology (Clifton, N.J.), 1693, 159–170. https://doi.org/10.1007/978-1-4939-7395-8_14

  9. Fathima, B., & Archer, A. C. (2021). Bacteriophage therapy: Recent developments and applications of a renaissant weapon. Research in Microbiology, 172(6), 103863. https://doi.org/10.1016/j.resmic.2021.103863

  10. Labrie, S. J., Samson, J. E., & Moineau, S. (2010). Bacteriophage resistance mechanisms. Nature reviews. Microbiology, 8(5), 317–327. https://doi.org/10.1038/nrmicro2315

  11. Clokie, M. R., Millard, A. D., Letarov, A. V., & Heaphy, S. (2011). Phages in nature. Bacteriophage, 1(1), 31–45. https://doi.org/10.4161/bact.1.1.14942

  12. Smith, H. W., & Huggins, M. B. (1982). Successful treatment of experimental Escherichia coli infections in mice using phage: its general superiority over antibiotics. Journal of general microbiology, 128(2), 307–318. https://doi.org/10.1099/00221287-128-2-307

  13. Schooley, R. T., Biswas, B., Gill, J. J., Hernandez-Morales, A., Lancaster, J., Lessor, L., Barr, J. J., Reed, S. L., Rohwer, F., Benler, S., Segall, A. M., Taplitz, R., Smith, D. M., Kerr, K., Kumaraswamy, M., Nizet, V., Lin, L., McCauley, M. D., Strathdee, S. A., Benson, C. A., … Hamilton, T. (2017). Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection. Antimicrobial agents and chemotherapy, 61(10), e00954-17. https://doi.org/10.1128/AAC.00954-17

  14. Ryan, E. M., Alkawareek, M. Y., Donnelly, R. F., & Gilmore, B. F. (2012). Synergistic phage-antibiotic combinations for the control of Escherichia coli biofilms in vitro. FEMS immunology and medical microbiology, 65(2), 395–398. https://doi.org/10.1111/j.1574-695X.2012.00977.x

  15. Kaur, S., Harjai, K., & Chhibber, S. (2012). Methicillin-resistant Staphylococcus aureus phage plaque size enhancement using sublethal concentrations of antibiotics. Applied and environmental microbiology, 78(23), 8227–8233. https://doi.org/10.1128/AEM.02371-12

  16. Jansen, M., Wahida, A., Latz, S., Krüttgen, A., Häfner, H., Buhl, E. M., Ritter, K., & Horz, H. P. (2018). Enhanced antibacterial effect of the novel T4-like bacteriophage KARL-1 in combination with antibiotics against multi-drug resistant Acinetobacter baumannii. Scientific reports, 8(1), 14140. https://doi.org/10.1038/s41598-018-32344-y

  17. Keen E. C. (2015). A century of phage research: bacteriophages and the shaping of modern biology. BioEssays : news and reviews in molecular, cellular and developmental biology, 37(1), 6–9. https://doi.org/10.1002/bies.201400152

  18. Joshua Chappie, PhD. (2017, February 22). Cornell University College of Veterinary Medicine. https://www.vet.cornell.edu/research/faculty/joshua-chappie-phd

  19. A first step toward liposome-mediated intracellular bacteriophage therapy

  20. Biotechnological applications of bacteriophages: state of the art

  21. Chhibber, S., Shukla, A., & Kaur, S. (2017). Transfersomal Phage Cocktail Is an Effective Treatment against Methicillin-Resistant Staphylococcus aureus-Mediated Skin and Soft Tissue Infections. Antimicrobial agents and chemotherapy, 61(10), e02146-16. https://doi.org/10.1128/AAC.02146-16

  22. Pirnay, J.-P., Ferry, T., & Resch, G. (2021). Recent progress toward the implementation of phage therapy in Western medicine. FEMS Microbiology Reviews, fuab040. https://doi.org/10.1093/femsre/fuab040

  23. Adaptive Phage Therapeutics, Inc. (2021). Randomized Open Label, Parallel Group, Controlled Study to Evaluate the Safety and Surgery Sparing Effect of Phage Therapy With Antibiotics for Patients With Prosthetic Joint Infections Who Are Candidates for Two Stage Exchange Arthroplasty (Clinical Trial Registration No. NCT04787250). clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT04787250

  24. Koff, J. (2021). CYstic Fibrosis bacterioPHage Study at Yale (CYPHY): A Single-site, Randomized, Double-blind, Placebo-controlled Study of Bacteriophage Therapy YPT-01 for Pseudomonas Aeruginosa Infections in Adults With Cystic Fibrosis (Clinical Trial Registration No. NCT04684641). clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT04684641

  25. Loganathan, A., Manohar, P., Eniyan, K., VinodKumar, C. S., Leptihn, S., & Nachimuthu, R. (2021). Phage therapy as a revolutionary medicine against Gram-positive bacterial infections. Beni-Suef University Journal of Basic and Applied Sciences, 10(1), 49. https://doi.org/10.1186/s43088-021-00141-8

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