Bacteriophage: Therapeutic Uses

Abstract

Bacteriophages are viruses that grow within bacteria. Almost all bacteriophages can destroy (lyse) their bacterial host, although many are ‘temperate’ and can insert their genome into that of their bacterial host, a state referred to as lysogeny. Those that can only kill their host bacteria are termed ‘virulent’ and are preferred for therapeutic use. Lysis kills the bacterial host and releases the next generation of bacteriophages. This unique property allows localised amplification of a bacteriophage therapeutic, but only where its specific bacterial host is present. Bacteriophages are also able to target bacteria living within biofilms that can make them highly refractory to conventional antibiotics. Since their discovery in 1915, bacteriophages have been identified as having potential for the control of bacterial disease. Following the widespread appearance of resistance to conventional antibiotics, interest in this area has revived and the results of clinical trials of bacteriophage therapeutics are now being reported.

Key Concepts:

  • Bacteriophages are viruses that infect bacteria.

  • Lytic bacteriophages kill their bacterial host rapidly, taking over host metabolism and producing a new generation of bacteriophages soon after infection.

  • Newly produced bacteriophages can infect new host bacteria locally and can also spread to other sites of infection.

  • This ability to kill bacteria led to their therapeutic use against bacterial infection in the pre‐antibiotic era.

  • In most of the world, bacteriophages have been superseded since the 1940s by chemical antibiotics due to a combination of factors, including the limited understanding of basic bacteriophage biology and the far broader host ranges of chemical antibiotics.

  • Despite many years of extensive clinical study in Eastern Europe and in earlier work in Europe and the United States, a lack of clinical trials meeting current regulatory requirements has limited the development of bacteriophage therapeutics.

  • Interest in bacteriophages as therapeutics has been revived by the looming antibiotic resistance crisis, in an era when much more information is available about the older work and when phage biology is far better understood.

  • Bacteriophage products for agricultural and food use are currently being marketed.

Keywords: bacteriophage; therapeutic; phage therapy; antibiotic; antibiotic resistance; biofilm; clinical trials

Figure 1.

Morphology of the tailed bacteriophages (Caudovirales). © AmpliPhi Biosciences.

Figure 2.

A tailed bacteriophage attached to its host cell. Reproduced from Brown JC (2003) Virology. In: Encyclopedia of Life Sciences. Chichester: Wiley. http://www.els.net/, doi:10.1038/npg.els.0000435

Figure 3.

Drawing of a tailed bacteriophage. Adapted from http://en.wikipedia.org/wiki/Image:Tevenphage.png. © Creative Commons Attribution ShareAlike 2.5 Licence.

Figure 4.

Bacteriophage lysis of the host cell. Reproduced from Brown JC (2003) Virology. In: Encyclopedia of Life Sciences. Chichester: Wiley. http://www.els.net/, doi:10.1038/npg.els.0000435

Figure 5.

Lytic cycle and lysogenic cycle. © Biocontrol Ltd.

Figure 6.

Use of bacteriophages to prevent cholera deaths in Assam, India, 1927–1931. Adapted from Summers WC (1999) Félix D'Herelle and the Origins of Molecular Biology. New Haven, CY: Yale University Press. Originally published in Morison J (1930) Indian Medical Gazette 60: 472–474.

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References

Abedon S, Kuhl S, Blasdel B and Kutter E (2011) Phage treatment of human infections. Bacteriophage 1: 66–85.

Alemayehu D, Casey PG, McAuliffe O et al. (2012) Bacteriophages ϕMR299‐2 and ϕNH‐4 can eliminate Pseudomonas aeruginosa in the murine lung and on cystic fibrosis lung airway cells. mBio 3: e00029–12.

Brüssow H (2012) What is needed for phage therapy to become a reality in Western medicine? Virology 434: 138–142.

Bruttin A and Brüssow H (2005) Human volunteers receiving E. coli phage T4 orally: a safety test of phage therapy. Antimicrobial Agents and Chemotherapy 49: 2874–2878.

Bruynoghe R and Maisin J (1921) Essais de therapeutique au moyen du bacteriophage du Staphylocoque. Comptes rendus des séances de la Société de biologie et de ses filiales 85: 1120–1121.

Buckling A and Brockhurst M (2012) Bacteria–virus coevolution. Advances in Experimental Medicine and Biology 751: 347–370.

Chanishvili N (2012) A Literature Review of the Practical Application of Bacteriophage Research. New York, NY: Nova Science Publishers.

Chibani‐Chennoufi S, Sidoti J, Dillmann M‐L et al. (2004) Isolation of bacteriophages from the stool of pediatric diarrhea patients. Journal of Bacteriology 186: 8287–8294.

Denou E, Bruttin A, Barretto C et al. (2009) T4 phages against Escherichia coli diarrhea: potential and problems. Virology 388: 21–30.

D'Herelle F (1919) Sur le role du microbe bacteriophage dans la typhose aviare. Comptes rendus de l'Académie des Sciences Paris 169: 932–934.

D'Herelle F (1922) The Bacteriophage: Its Role in Immunity, translated to English by Dr. George H. Smith, PhD. Baltimore: Williams and Wickens Co. Waverly Press.

Dubos RJ, Straus JH and Pierce C (1943) The multiplication of bacteriophage in vivo and its protective effect against an experimental infection with Shigella dysenteriae. Journal of Experimental Medicine 78: 161–168.

Duckworth DH (1976) Who discovered bacteriophage? Bacteriological Reviews 40: 793–802.

Eaton MD and Bayne‐Jones S (1934) Bacteriophage therapy: review of the principles and results of the use of bacteriophage in the treatment of infections (I). Journal of the American Medical Association 103: 1769–1776, 1847–1853, 1934–1939.

Fruciano DE (2007) Phage as an antimicrobial agent: d'Herelle's heretical theories and their role in the decline of phage prophylaxis in the West. Canadian Journal of Infectious Diseases & Medical Microbiology 18: 19–26.

Knouf EG, Ward WE, Reichle PA et al. (1946) Treatment of typhoid fever with type specific bacteriophage. Journal of the American Medical Association 132: 134–138.

Kutter E, De Vos D, Gvasalia G et al. (2010) Phage therapy in clinical practice: treatment of human infections. Current Pharmaceutical Biotechnology 11: 69–86.

Kutter E, Gvasalia G, Alavidze Z and Brewster E (2013) Phage therapy. In: Grassberger M, Sherman RA, Gileva OS, Kim CMH and Mumcuoglu KY (eds), Biotherapy – History, Principles and Practice, pp. 191–231. New York: Springer.

Lu TK and Koeris MS (2011) The next generation of bacteriophage therapy. Current Opinion in Microbiology 14(5): 524–531.

MacNeal WJ, Frisbee FC and McRae MA (1942) Staphylococcemia 1931–1940: five hundred patients. American Journal of Clinical Pathology 12: 281–294.

Marza JA, Soothill JS, Boydell P and Collyns TA (2006) Multiplication of therapeutically administered bacteriophages in Pseudomonas aeruginosa infected patients. Burns 32: 644–646.

McCallin S, Sarker SA, Barretto C et al. (2013) Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects. Virology 443: 187–196.

Merabishvili M, Pirnay J‐P, Verbeken G et al. (2009) Quality‐controlled small‐scale production of a well‐defined bacteriophage cocktail for use in human clinical trials. PLoS ONE 4(3): e4944.

Mutnick AH, Enne V and Jones RN (2003) Linezolid resistance since 2001: SENTRY Antimicrobial Surveillance Program. Annals of Pharmacotherapy 37: 769–774.

Pearl S, Gabay C, Kishony R, Oppenheim A and Balaban NQ (2008) Nongenetic individuality in the host–phage interaction. PLoS Biology 6: 0957–0964.

Pirnay J‐P, Verbeken G, Rose T et al. (2012) Introducing yesterday's phage therapy in today's medicine. Future Virology 7: 379–390.

Rhoads DD, Wolcott RD, Kuskowski MA et al. (2009) Bacterophage therapy of venous leg ulcers in humans: results of a phase I safety trial. Journal of Wound Care 18(6): 237–243.

Ryan EM, Alkawareek MY, Donnelly RF and Gilmore BF (2012) Synergistic phage‐antibiotic combinations for the control of Escherichia coli biofilms in vitro. FEMS Immunology & Medical Microbiology 65: 395–398.

Sarker SA, McCallin S, Baretto C et al. (2012) Oral T4‐like phage cocktail application to healthy adult volunteers from Bangladesh. Virology 434: 222–232.

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 (Warsz) 35: 569–583.

Smith HW and Huggins RB (1982) Successful treatment of experimental E. coli infections in mice using phage: its general superiority over antibiotics. Journal of General Microbiology 128: 307–318.

Smith HW and Huggins RB (1987) The control of experimental E. coli diarrhea in calves by means of bacteriophage. Journal of General Microbiology 133: 1111–1126.

Soothill JS (1992) Treatment of experimental infections of mice with bacteriophages. Journal of Medical Microbiology 37: 258–261.

Soothill JS (1994) Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa. Burns 20: 209–211.

Soothill JS, Hawkins C, Anggard EA and Harper DR (2004) Therapeutic use of bacteriophages. Lancet Infectious Diseases 4: 544–545.

Streptomycin in Tuberculosis Trials Committee (1948) Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation. British Medical Journal 2 (4582): 769–782.

Summers WC (1993) Cholera and plague in India: the bacteriophage inquiry of 1927–1936. Journal of the History of Medicine and Allied Sciences 48: 275–301.

Theuretzbacher U (2012) Accelerating resistance, inadequate antibacterial drug pipelines and international responses. International Journal of Antimicrobial Agents 39: 295–299.

Wright A, Hawkins C, Änggård E and Harper D (2009) A controlled clinical trial of a therapeutic bacteriophage in chronic otitis due to antibiotic‐resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clinical Otolaryngology 34(4): 349–357.

Further Reading

Harper DR, Anderson J and Enright MC (2011) Phage therapy: delivering on the promise. Therapeutic Delivery 2: 935–947.

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Harper, David R, Burrowes, Benjamin H, and Kutter, Elizabeth M(Aug 2014) Bacteriophage: Therapeutic Uses. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020000.pub2]