Bacteriophage Therapy: A Resurgent Alternative in the Era of Antibiotic Resistance
DOI:
https://doi.org/10.33687/ricosbiol.03.06.64Keywords:
antibiotic resistance, bacteriophages, phage therapy, clinical applications, genetic engineering, innovations, multidrug-resistant bacteriaAbstract
Phage therapy, the use of bacteriophages to combat bacterial infections, is experiencing a significant resurgence driven by the escalating crisis of antibiotic resistance. This review provides a comprehensive overview of the evolution of phage therapy, from its early 20th-century origins and subsequent decline to its current status as a promising alternative or adjunct to conventional antibiotics. We examine the fundamental mechanisms of phage action, highlighting their specificity for bacterial targets and their lytic capabilities against even multi-drug resistant strains, while often sparing the host microbiota. Current applications are explored across various domains, including the treatment of chronic and resistant infections in humans, personalised medicine approaches, veterinary uses, and food safety applications. Key innovations, fueled by advances in genomics and synthetic biology, such as phage engineering, cocktail formulations, phage-derived enzymes (e.g., endolysins), and novel delivery systems, are discussed as crucial enhancers of therapeutic potential. Despite its promise, phage therapy faces significant challenges, including complex regulatory pathways, manufacturing and standardisation hurdles, the potential for bacterial resistance to phages, and host immune responses. Addressing these limitations through rigorous clinical trials, standardized protocols, and continued research is essential. This review underscores the critical need to integrate phage therapy into modern medical paradigms as a vital tool in the global fight against antibiotic-resistant infections, outlining future directions for research and clinical implementation.
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References
Cahill, J., and Young, R. (2019). Phage lysis: Multiple genes for multiple barriers. Advances in Virus Research, 103, 33–70. https://doi.org/10.1016/bs.aivir.2018.09.003
Chan, B. K., Abedon, S. T., and Loc-Carrillo, C. (2013). Phage cocktails and the future of phage therapy. Expert Review of Anti-infective Therapy, 11(8), 755–760. https://doi.org/ 10.1586/14787210.2013.819725
Chaudhry, W. N., Concepción-Acevedo, J., Park, T., Andleeb, S., Bull, J. J., and Levin, B. R. (2017). Synergy and order effects of antibiotics and phages in killing Pseudomonas aeruginosa biofilms. PLoS One, 12(1), e0168615. https://doi.org/10.1371/journal.pone. 0168615
Clark, J. R., and March, J. B. (2004). Bacteriophage-mediated nucleic acid immunisation. FEMS Immunology and Medical Microbiology, 40(1), 21–26. https://doi.org/10.1016/ S0928-8244(03)00301-6
Comeau, A. M., Tétart, F., Trojet, S. N., Prère, M. F., and Krisch, H. M. (2007). Phage-antibiotic synergy (PAS): β-lactam and quinolone antibiotics stimulate virulent phage growth. PLoS One, 2(8), e799. https://doi.org/10.1371/journal.pone.0000799
Endersen, L., O’Mahony, J., Hill, C., Ross, R. P., McAuliffe, O., and Coffey, A. (2014). Phage therapy in the food industry. Annual Review of Food Science and Technology, 5, 327– 349. https://doi.org/10.1146/annurev-food-030713-092415
Fabijan, A. P., Lin, R. C. Y., Ho, J., Maddocks, S., Khatami, A., Lam, M., ... and Iredell, J. R. (2020). Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nature Microbiology, 5(3), 465–472. https://doi.org/10.1038/s41564-019-0634-z
Fischetti, V. A. (2005). Bacteriophage lytic enzymes: Novel anti-infectives. Trends in Microbiology, 13(10), 491–496. https://doi.org/10.1016/j.tim.2005.08.007
Fruciano, D. E., and Bourne, S. (2020). Phage therapy for animal health: Focus on aquaculture. Viruses, 13(1), 1. https://doi.org/10.3390/v13010001
Goodridge, L. D., and Abedon, S. T. (2003). Bacteriophage therapy for food safety: Challenges and opportunities. Current Opinion in Biotechnology, 14(3), 294–301. https:// doi.org/10.1016/s0958-1669(03)00062-9
Górski, A., Międzybrodzki, R., Węgrzyn, G., Jończyk-Matysiak, E., Borysowski, J., and Weber-Dąbrowska, B. (2016). Phage therapy: Combating infections with potential for evolving from merely a last resort to systematic application. Cellular and Molecular Life Sciences, 73(23), 4473–4491. https://doi.org/10.1007/s00018-016-2286-7
Hatfull, G. F., Dedrick, R. M., and Schooley, R. T. (2022). Phage therapy for antibiotic- resistant bacterial infections. Annual Review of Medicine, 73, 197–211. https://doi.org/ 10.1146/annurev-med-012221-083637
Hodyra-Stefaniak, K., Miernikiewicz, P., Drapała, J., Drab, M., Jonczyk-Matysiak, E., Lecion, D., ... and Górski, A. (2015). Mammalian host-versus-phage immune response determines phage fate in vivo. Scientific Reports, 5, 11174. https://doi.org/10.1038/ srep11174
Howard-Varona, C., Hargreaves, K. R., Abedon, S. T., and Sullivan, M. B. (2017). Lysogeny in nature: Mechanisms, impact and ecology of temperate phages. The ISME Journal, 11(7), 1511–1520. https://doi.org/10.1038/ismej.2017.16
Jault, P., Leclerc, T., Jennes, S., Pirnay, J. P., Que, Y. A., Resch, G., ... and PhagoBurn study group. (2019). Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): A randomised, controlled, double-blind phase 1/2 trial. The Lancet Infectious Diseases, 19(1), 35–45. https:// doi.org/10.1016/S1473-3099(18)30482-1
Jones, J. B., Jackson, L. E., Balogh, B., Obradovic, A., Iriarte, F. B., and Momol, M. T. (2007). Bacteriophages for plant disease control. Annual Review of Phytopathology, 45, 245– 262. https://doi.org/10.1146/annurev.phyto.45.062806.094444
Jończyk-Matysiak, E., Weber-Dąbrowska, B., Owczarek, B., Międzybrodzki, R., Łusiak- Szelachowska, M., and Górski, A. (2021). Phage therapy in veterinary medicine: A historical and modern perspective. Antibiotics (Basel), 10(6), 680. https://doi.org/10.3390/ antibiotics10060680
Labrie, S. J., Samson, J. E., and Moineau, S. (2010). Bacteriophage resistance mechanisms.
Nature Reviews Microbiology, 8(5), 317–327. https://doi.org/10.1038/nrmicro2315
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, 8(3), 162–173. https://doi.org/10.4292/wjgpt.v8.i3.162
Loc-Carrillo, C., and Abedon, S. T. (2011). Pros and cons of phage therapy. Bacteriophage, 1(2), 111–114. https://doi.org/10.4161/bact.1.2.14590
Malik, D. J., Sokolov, I. J., Vinner, G. K., Mancuso, F., Cinquerrui, S., Clokie, M. R. J., ... and Garton, N. J. (2017). Formulation, stabilisation and encapsulation of bacteriophage for phage therapy. Advances in Colloid and Interface Science, 249, 100–133. https://doi.org/ 10.1016/j.cis.2017.05.014
Merabishvili, M., Pirnay, J. P., Verbeken, G., Chanishvili, N., Tediashvili, M., Lashkhi, N., ... and De Vos, D. (2009). Quality-controlled small-scale production of a well-defined bacteriophage cocktail for use in human clinical trials. PLoS One, 4(3), e4944. https:// doi.org/10.1371/journal.pone.0004944
Miedzybrodzki, R., Borysowski, J., Weber-Dabrowska, B., Fortuna, W., Letkiewicz, S., Szufnarowski, K., Pawełczyk, Z., Rogóż, P., Kłak, M., Wojtasik, E., and Górski, A. (2012). Clinical aspects of phage therapy. Advances in Virus Research, 83, 73–121. https:// doi.org/10.1016/B978-0-12-394438-2.00003-7
Nilsson, A. S. (2014). Phage therapy--constraints and possibilities. Upsala Journal of Medical Sciences, 119(2), 192–198. https://doi.org/10.3109/03009734.2014.902878
Pande, J., Szewczyk, M. M., and Grover, A. K. (2010). Phage display: Concept, innovations, applications and future. Biotechnology Advances, 28(6), 849–858. https://doi.org/ 10.1016/j.biotechadv.2010.07.004
Pelfrene, E., Willebrand, E., Cavaleiro Sanches, A., Sebris, Z., and Cavaleri, M. (2016). Bacteriophage therapy: a regulatory perspective. Journal of Antimicrobial Chemotherapy, 71(8), 2071–2074. https://doi.org/10.1093/jac/dkw157
Peng, H., and Chen, I. A. (2021). Phage-based diagnostic and therapeutic applications. International Journal of Molecular Sciences, 22(10), 5145. https://doi.org/10.3390/ ijms22105145
Pires, D. P., Cleto, S., Sillankorva, S., Azeredo, J., and Lu, T. K. (2016). Genetically engineered phages: A review of advances over the last decade. Microbiology and Molecular Biology Reviews, 80(3), 523–543. https://doi.org/10.1128/MMBR.00069-15
Pirnay, J. P., De Vos, D., Verbeken, G., Merabishvili, M., Chanishvili, N., Vaneechoutte, M., ... and Lavigne, R. (2011). The phage therapy paradigm: Prêt-à-porter or sur-mesure? Pharmaceutical Research, 28(4), 934–937. https://doi.org/10.1007/s11095-010-0313-5
Principi, N., Silvestri, E., and Esposito, S. (2019). Phage therapy: An additional weapon in the armamentarium against multidrug-resistant bacterial infections? Frontiers in Pharmacology, 10, 194. https://doi.org/10.3389/fphar.2019.00194
Puapermpoonsiri, M., Spencer, J., and van der Walle, C. F. (2009). A freeze-dried formulation of bacteriophage K: An alternative approach to treating Staphylococcus aureus infections. European Journal of Pharmaceutics and Biopharmaceutics, 71(2), 222–229. https://doi.org/10.1016/j.ejpb.2008.09.011
Rhoads, D. D., Wolcott, R. D., Kuskowski, M. A., Wolcott, B. M., Ward, L. S., and Sulakvelidze, A.(2009). Bacteriophage therapy of venous leg ulcers in humans: Results of a phase I safety trial. Journal of Wound Care, 18(6), 237–243. https://doi.org/10.12968/jowc. 2009.18.6.42801
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., Aslam, S., and 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
Segall, A. M., Roach, D. R., and Strathdee, S. A. (2019). New frontiers: phage therapy against bacterial pathogens of the opioid epidemic. Drug and Alcohol Dependence, 198, 1–5. https://doi.org/10.1016/j.drugalcdep.2019.02.016
Smith, G. P. (1985). Filamentous fusion phage: Novel expression vectors that display cloned antigens on the virion surface. Science, 228(4705), 1315–1317. https://doi.org/ 10.1126/science.4001944
Sulakvelidze, A., Alavidze, Z., and Morris, J. G., Jr. (2001). Bacteriophage therapy. Antimicrobial Agents and Chemotherapy, 45(3), 649–659. https://doi.org/10.1128/AAC. 45.3.649-659.2001
Summers, W. C. (1999). Félix d’Herelle and the origins of molecular biology. Yale University Press.
Tagliaferri, T. L., Compagnone, M., Sahi, J. S., Riello, G., Von Arx, C., and Ruga, S. (2021). Phage-antibiotic combination therapy: State of the art and future perspectives. Critical Reviews in Microbiology, 47(6), 719–736. https://doi.org/10.1080/1040841X.2021.1969869
Verbeken, G., Pirnay, J. P., De Vos, D., Jennes, S., Zizi, M., Lavigne, R., ... and Huys, I. (2014). Optimizing bacteriophage therapy: In vivo studies matter. Expert Review of Anti-infective Therapy, 12(7), 753–757. https://doi.org/10.1586/14787210.2014.915687
World Health Organization. (n.d.). Antibiotic resistance. Retrieved June 2, 2025, from https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
Yacoby, I., Bar, H., and Benhar, I. (2007). Targeted cancer therapy by employing engineered bacteriophages. Proceedings of the National Academy of Sciences of the United States of America, 104(45), 17950–17955. https://doi.org/10.1073/pnas.0704112104
Yosef, I., Manor, M., Kiro, R., and Qimron, U. (2015). Temperate and lytic bacteriophages programmed to sensitize bacteria to antibiotics. Proceedings of the National Academy of Sciences of the United States of America, 112(14), 4266–4271. https://doi.org/10.1073/ pnas.1500107112
Young, R. (1992). Bacteriophage lysis: Mechanism and regulation. Microbiological Reviews, 56(3), 430–481. https://doi.org/10.1128/mr.56.3.430-481.1992
Łusiak-Szelachowska, M., Żaczek, M., Weber-Dąbrowska, B., Międzybrodzki, R., Kłak, M., Fortuna, W., ... and Górski, A. (2014). Phage neutralization by sera of patients receiving phage therapy. Viral Immunology, 27(6), 295–304. https://doi.org/10.1089/vim.2013.0128
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