A Look at Phage Therapy One Hundred Years After the Bacteriophages Discovery

  • T. S. Ilyina
  • E. R. Tolordava
  • Yu. M. RomanovaEmail author


This overview discusses the literature data on the use of bacteriophages in the treatment of both acute and chronic infectious diseases caused by antibiotic-resistant pathogens. Traditionally, phage therapy is based on the use of naturally occurring phages for infection and lysis of bacteria at the site of infection. It has fundamental advantages over antibiotic therapy. At the same time, it has some disadvantages. Currently, the application of biotechnological methods, such as the development of the recombinant bacteriophages, makes it possible to eliminate the shortcomings of antimicrobial phage therapy and to expand its opportunities due to the use of lytic proteins of phages and their modified derivatives.


bacteriophages phage therapy lytic proteins of phages antibiotic and phage resistance an alternative to antibiotics 



This study had no specific financial support.


This article does not contain any studies involving animals or human beings performed by any of the authors.


The authors declare that they have no conflict of interest.


  1. 1.
    Ackermann, H.-W. and Prangishvilli, D., Prokaryote viruses studied by electron microscopy, Arch. Virol., 2012, vol. 157, pp. 1843–1849. PMID: 22752841. Scholar
  2. 2.
    Lwoff, A., Lysogeny, Bacteriol. Rev., 1953, vol. 17, pp. 269–337. PMID 13105613.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Adams, M.H., Bacteriophages, New York: Interscience Publ., 1959.Google Scholar
  4. 4.
    Siringan, P., Connerton, P.L., Cummings, N.J., and Connerton, L.F., Alternative bacteriophage life cycles: The carrier state of Campylobacter jejuni, Open Biol., 2014, vol. 4, p. 130200. PMID: 24671947. Scholar
  5. 5.
    Abedon, S.T., Kuhl, S.J., Blasdel, B.G., and Kutter, E.M., Phage treatment of human infections, Bacteriophage, 2011, vol. 1, pp. 66–85. PMID: 22334863. Scholar
  6. 6.
    Kutateladze, M. and Adamia, R., Bacteriophages as potential new therapeutics or supplement antibiotics, Trends Biotechnol., 2010, vol. 28, pp. 591–595. PMID: 20810181. Scholar
  7. 7.
    Sulakvelidze, A., Alavidze, Z., and Morris, J.G., Jr., Bacteriophage therapy, Antimicrob. Agents Chemother., 2001, vol. 45, pp. 649–659.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Chanishvili, N., A Literature Review of the Practical Application of Bacteriophage Research, Hauppauge, NY: Nova Science Publ., 2012.Google Scholar
  9. 9.
    Cisek, A., Dabrowska, I., Gregorczyk, K., and Wyzewski, Z., Phage therapy in bacterial infections treatment. One hundred years after the discovery of bacteriophages, Curr. Microbiol., 2016, vol. 74, pp. 277–283.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    WHO (World Health Organization). Antimicrobial Resistance: Global Report on Surveillance, Geneva: World Health Organization, 2014.Google Scholar
  11. 11.
    Shurma, S., Chatterjee, S., Datta, S., Prasad, R.K., and Vaizala, M.G., Bacteriophages and their applications: An overview, Folia Microbiol., 2016, vol. 62, pp. 17–55.CrossRefGoogle Scholar
  12. 12.
    Lin, D.M., Koskella, B., and Lin, H.C., Phago-therapy: An alternative to antibiotics in the age of multi-drug resistance, World J. Gastrointest. Pharmacol. Ther., 2017, vol. 8, no. 3, pp. 162–173.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Abedon, S.T., Ecology of anti-biofilm agents I: Antibiotics versus bacteriophages, Pharmaceuticals (Basel), 2015, vol. 8, no. 3, pp. 525–558.CrossRefGoogle Scholar
  14. 14.
    Gill, J.J. and Hyman, P., Phage choice, isolation, and preparation for phage therapy, Curr. Pharm. Biotechnol., 2010, vol. 11, pp. 2–14.PubMedCrossRefGoogle Scholar
  15. 15.
    Chan, B.K., Abedon, S.T., and Loc-Carillo, C., Phage cocktails and the future of phage therapy, Future Microbiol., 2013, vol. 8, pp. 769–783.PubMedCrossRefGoogle Scholar
  16. 16.
    Monteiro, R., Pires, D.P. and Costa, A.R., Phage Therapy: Going Temporate?, Trends Microbiol., 2019, vol. 27, no. 4, p. 378.CrossRefGoogle Scholar
  17. 17.
    Golkar, Z., Bagasra, O., and Pace, D.G., Bacteriophage therapy: A potential solution for the antibiotic resistance crisis, J. Infect. Dev. Countries, 2014, vol. 8, pp. 129–136.CrossRefGoogle Scholar
  18. 18.
    Kutataladze, M., Experience of the Eliava Institute in bacteriophage therapy, Virol. Sin., 2015, vol. 30, pp. 80–81.CrossRefGoogle Scholar
  19. 19.
    Nilsson, A.S., Phage therapy–constraints and possibilities, Upsala J. Med. Sci., 2014, vol. 119, pp. 192–198.PubMedCrossRefGoogle Scholar
  20. 20.
    Labrie, J., Samson, J.E., and Moineau, S., Bacteriophage resistance mechanisms, Nat. Rev., 2010, vol. 8, pp. 317–327.Google Scholar
  21. 21.
    Goldfarb, T., Sberro, H., Weinstock, W., Cohen, O., Doron, S., et al., BREX, a phage resistance system widespread in microbial genomes, EMBO J., 2015, vol. 34, pp. 169–183.PubMedCrossRefGoogle Scholar
  22. 22.
    van Houte, S., Buckling, A., and Westra, E.R., Evolutionary ecology of prokaryotic immune mechanisms, Microbiol. Mol. Biol. Rev., 2016, vol. 80, no. 3, pp. 745–760.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Doron, S., Melamed, S., Ofir, G., Leavitt, A., Lopatina, A., et al., Systematic discovery of antiphage defense systems in the microbial pangenome, Science, 2018, vol. 359, no. 6379, p. eaar4120.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Ofir, G., Melamed, S., Sberro, H., Mukamel, Z., Silverman, S., et al., DISARM is a widespread bacterial defense system with broad anti-phage activities, Nat. Microbiol., 2018, vol. 3, no. 1, pp. 90–98.PubMedCrossRefGoogle Scholar
  25. 25.
    Gasiunas, G., Sinkunas, T., and Siksnys, V., Molecular mechanisms of CRISPR-mediated microbial immunity, Cell. Mol. Life Sci., 2014, vol. 71, pp. 449–465.PubMedCrossRefGoogle Scholar
  26. 26.
    Barrangou, R. and Oost, J., Bacteriophage exclusion, a new defense system, EMBO J., 2015, vol. 34, no. 2, pp. 134–135.PubMedCrossRefGoogle Scholar
  27. 27.
    Hanlon, G.W., Bacteriophages: An appraisal of their role in the treatment of bacterial infections, Int. J. Antimicrob. Agents, 2007, vol. 30, pp. 118–128.PubMedCrossRefGoogle Scholar
  28. 28.
    Bondy-Denomy, J., Pawluck, A., Maxwell, K.L., and Davidson, A.R., Bacteriophage genes that inactivate the CRISPR-Cas bacterial immune system, Nature, 2013, vol. 493, pp. 429–432.PubMedCrossRefGoogle Scholar
  29. 29.
    Borges, A.L., Davidson, A.R., and Bondy-Denomy, J., The discovery, mechanisms and evolutionary impact of anti-CRISPRs, Annu. Rev. Virol., 2017, vol. 4, no. 1, pp. 37–59. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Murphy, J., Mahony, J., Ainsworth, S., Nauta, A., and van Sinderen, D., Bacteriophage orphan DNA methyltransferases: insights from their bacterial origin, function, and occurrence, Appl. Environ. Microbiol., 2013, vol. 79, no. 24, pp. 7547–7555.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Costerton, J.W., Introduction to biofilm, Int. J. Antimicrob. Agents, 1999, vol. 11, pp. 217–221.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Parasion, S., Kwiatek, M., Gryko, R., Mizak, L., and Malm, A., Bacteriophages as an alternative strategy for fighting biofilm development, Pol. J. Microbiol., 2014, vol. 63, no. 2, pp. 137–145.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Romanova, Yu.M., Mulabaev, N.S., Tolordava, E.R., Seregin, A.V., Seregin, I.V., Alexeeva, N.V., Stepanova, T.V., Levina, G.A., Barkhatova, O.I., Gamova, N.A., Goncharova, S.A., Didenko, L.V., and Rakovskaya, I.V., Microbial communities on kidney stones, Mol. Genet., Microbiol. Virol., 2015, vol. 30, no. 2, pp. 78–84.CrossRefGoogle Scholar
  34. 34.
    Costerton, J.W., Stewart, P.S., and Greenberg, E.P., Bacterial biofilms: a common cause of persistent infections, Science, 1999, vol. 284, pp. 1318–1322.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Azeredo, J. and Sutherland, I.W., The use of phages for the removal of infections biofilms, Curr. Pharm. Biotechnol., 2008, vol. 9, pp. 261–266.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Abedon, S.T., Ecology of anti-biofilm agents I: Antibiotics versus bacteriophages, Pharmaceuticals (Basel), 2015, vol. 8, no. 3, pp. 525–558.CrossRefGoogle Scholar
  37. 37.
    Różalska, B., Walecka, E., and Sadowska, B., Wykrywanie biofilmów stanowiących problemy medyczne i perspektywy ich eradykacji, Zakażenia, 2010, vol. 10, pp. 13–21.Google Scholar
  38. 38.
    Dryukker, V.V. and Gorshkova, A.S., Bacteriophages and their functioning in the biofilms, Izv. Irkutsk.Gos. Univ. Ser. Biol. Ekol., 2012, vol. 5, no. 3, pp. 8–16.Google Scholar
  39. 39.
    Adhya, S., Merril, C.R., and Biauas, B., Therapeutic and prophylactic applications of bacteriophage components in modern medicine, Cold Spring Harbor Perspect. Med., 2014, vol. 4, p. a012518.CrossRefGoogle Scholar
  40. 40.
    Donlan, R.M., Preventing biofilms of clinically relevant organisms using bacteriophages, Trends Microbiol., 2009, vol. 17, pp. 66–72.PubMedCrossRefGoogle Scholar
  41. 41.
    Whitchurch, C.B., Tolker-Nielsen, T., Ragas, P.S., and Mattick, J.S., Extracellular DNA required for bacterial biofilm formation, Science, 2002, vol. 295, no. 5559, p. 1487.PubMedCrossRefGoogle Scholar
  42. 42.
    Pires, D.P., Cleto, S., Sillancorva, S., Azeredo, J., and Lu, T.K., Genetically engineered phages: a review of advances over the last, Microbiol. Mol. Biol. Rev., 2016, vol. 80, no. 3, pp. 523–542.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Pires, D.P., Melo, L., Vilas Boas, D., Sillancorva, S., and Azeredo, J., Phage therapy as an alternative or complementary strategy to prevent and control biofilm-related infections, Curr. Opin. Microbiol., 2017, vol. 39, pp. 48–56.PubMedCrossRefGoogle Scholar
  44. 44.
    Gu, J., Liu, X., Li, Y., Han, W., Lei, L., et al., A method for generation cocktail with great therapeutic potential, PLoS One, 2012, vol. 7, p. e31698.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Jaiswal, A., Koley, H., Ghosh, A., Palit, A., and Sarkar, B., Efficacy of cocktail phage therapy in treating Vibrio cholerae infection in rabbit model, Microbiol. Infect., 2013, vol. 15, pp. 152–156.CrossRefGoogle Scholar
  46. 46.
    Chan, B.K. and Abedon, S.T., Phage therapy pharmacology phage cocktails, Adv. Appl. Microbiol., 2012, vol. 78, pp. 1–23.PubMedCrossRefGoogle Scholar
  47. 47.
    Chan, K., Abedon, S.T., and Los-Carillo, C., Phage cocktails and the future of phage therapy, Future Microbiol., 2013, vol. 8, p. 6.CrossRefGoogle Scholar
  48. 48.
    Al-Wrafy, F., Brzozouska, E., Gorska, S., and Gamian, A., Pathogenic factors of Pseudomonas aeruginosa–the role of biofilm in pathogenicity and as a target for phage therapy, Postepy Hig. Med. Dosw. (Online), 2016, vol. 70, pp. 78–91.Google Scholar
  49. 49.
    Valerio, N., Oliveira, C., Jesus, V., Branco, T., Pereira, C., et al., Effects of single and combined use of bacteriophages and antibiotics to inactivate E. coli, Virus Res., 2017, vol. 240, pp. 8–17.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Domingo-Calap, P. and Delgado-Martinez, J., Bacteriophages: Protagonists of a post-antibiotic era, Antibiotics, 2018, vol. 7, pp. 66–82.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Torres-Barcelo, C. and Hochberg, M., Evolutionary rationale for phages as complements of antibiotics, Trends Microbiol., 2016, vol. 24, pp. 249–256.PubMedCrossRefGoogle Scholar
  52. 52.
    Comean, A., Tetart, F., Trojet, S., Prere, M., and Krisch, H., La “synergie phage-antibiotiques”, Med. Sci., 2008, vol. 24, pp. 449–451.Google Scholar
  53. 53.
    Wittebole, X., De Roock, S., and Opal, S., A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens, Virulence, 2013, vol. 5, pp. 226–235.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Lu, T.K. and Collins, J.J., Dispersing biofilms with engineered enzymatic bacteriophages, Proc. Natl. Acad. Sci. U. S. A., 2007, vol. 104, pp. 11197–11202.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Itoh, Y., Wang, Y., Hinnesbush, B.J., Preston, J.F., and Romeo, T., Depolymerization of beta-1,6-N-acetil-D-glucosamin disrupts the integrity of diverse bacterial biofilms, J. Bacteriol., 2005, vol. 187, pp. 382–387.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Ando, H., Lemire, S., Pires, D.P., and Lu, T.K., Engineering modular viral scaffolds for targeted bacterial population editing, Cell Syst., 2015, vol. 1, pp. 187–196.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Gladstone, E.G., Molineux, I.J., and Bull, J.J., Evolutionary principles and synthetic biology: Avoiding a molecular tragedy of the commons with an engineered phage, J. Biol. Eng., 2012, vol. 6, p. 13.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Drulis-Kawa, Z., Majkowska-Strobek, G., Maciejewska, B., Delattre, A.-S., and Lavigne, R., Learning from bacteriophages–advantages and limitations of phage and phage-encoded protein applications, Curr. Protein Pept. Sci., 2012, vol. 13, pp. 699–722.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Pires, D.P., Oliveira, H., Melo, L.D., Sillankorva, S., and Azeredo, J., Bacteriophage-encoded depolymerases: Their diversity and biotechnological applications, Appl. Microbiol. Biotechnol., 2016, vol. 100, no. 5, pp. 2141–2151.PubMedCrossRefGoogle Scholar
  60. 60.
    Latka, A., Maciejewska, B., Majkowska-Skrobek, G., Briers, Y., and Drulis-Kana, Z., Bacteriophage encoded virion-associated enzymes to overcome the carbohydrate barriers during the infection process, Appl. Microbiol. Biotechnol., 2017, vol. 101, pp. 3103–3119.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Rodriguez-Rubio, L., Martinez, B., Donovan, D., Rodriguez, A., and Garcia, P., Bacteriophage virion-associated peptidoglycan hydrolases: Potential new enzybiotics, Crit. Rev. Microbiol., 2013, vol. 39, pp. 427–434.PubMedCrossRefGoogle Scholar
  62. 62.
    Nelson, D., Loomis, L., and Fischetti, V.A., Prevention and elimination of upper respiratory colonization of mice by group A streptococci by using a bacteriophage lytic enzyme, Proc. Natl. Acad. Sci. U. S. A., 2001, vol. 98, pp. 4107–4112.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Nelson, D.C., Schmelcher, M., Rodriguez-Rubio, L., Klumpp, J., and Pritchard, D.G., Endolysins as antimicrobials, Adv. Virus Res., 2012, vol. 83, pp. 299–365.PubMedCrossRefGoogle Scholar
  64. 64.
    Vazquez, R., Demenech, M., Iglesias-Bexiga, M., Menendez, M., and Garcia, P., Csl2, a novel chimeric bacteriophage lysine to fight infections caused by Streptococcus suis, an emerging zoonotic pathogen, Sci. Rep., 2017, vol. 7, p. 16506.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Borysowski, J., Weber-Dabrowska, B., and Gorski, A., Bacteriophage endolysins as a novel class of antibacterial agents, Exp. Biol. Med., 2006, vol. 231, pp. 366–377.CrossRefGoogle Scholar
  66. 66.
    Fischetti, V.A., Bacteriophage lysins as effective antibacterials, Curr. Opin. Microbiol., 2008, vol. 11, pp. 393–400.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Fischetti, V.A., Development of phage lysins as novel therapeutics: a historical perspective, Viruses, 2018, vol. 10, pp. 310–319.PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Haddad Kashani, H., Schmelcher, M., Sabzalipoor, H., Seyed Hosseini, E., and Moniri, R., Recombinant endolysins as potential therapeutics against antibiotic-resistant Staphylococcus aureus: Current status of research and novel delivery strategies, Clin. Microbiol. Rev., 2017, vol. 31, no. 1, p. e00071-17.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Gersmans, H., Criel, B., and Briers, Y., Synthetic biology of modular endolysins, Biotechnol. Adv., 2018, vol. 36, no. 3, pp. 624–640.CrossRefGoogle Scholar
  70. 70.
    Schmelchar, M., Donovan, D.M., and Loessner, M.J., Bacteriophage endolysins as novel antimicrobials, Future Microbiol., 2012, vol. 7, pp. 1147–1171.CrossRefGoogle Scholar
  71. 71.
    Chen, B.K. and Abedon, S.T., Bacteriophages and their enzymes in biofilm control., Curr. Pharm. Des., 2015, vol. 21, pp. 85–99.CrossRefGoogle Scholar
  72. 72.
    Roach, D.R. and Donovan, D.M., Antimicrobial bacteriophage-derived proteins and therapeutic applications, Bacteriophage, 2015, vol. 5, p. e1062590.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Sao-Jose, C., Engineering of phage-derived enzymes: improving their potential as antimicrobials, Antibiotics, 2018, vol. 7, pp. 29–60.PubMedCentralCrossRefPubMedGoogle Scholar
  74. 74.
    Yang, H., Yu, J., and Wei, H., Engineered bacteriophage lysins as novel anti-infectives, Front. Microbiol., 2014, vol. 5, p. 542.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Totte, J.E.E., van Doom, M.B., and Pasma, S.G.M.A., Successful treatment of chronic Staphylococcus aureus-related dermatoses with the topical endolysin staphefekt SA100: A report of 3 cases, Case Rep. Dermatol., 2017, vol. 9, pp. 19–25.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Jun, S.Y., Jang, I.J., Yoon, S., Jang, K., Yu, K.-S., et al., Pharmacokinetics and tolerance of the phage endolysin-based candidate drug SAL200 after a single intravenous administration among healthy volunteers, Antimicrob. Agents Chemother., 2017, vol. 61, p. e02629-16.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Mosiejewska, B., Olszak, T., and Drulis-Kawa, Z., Application of bacteriophages versus phage enzymes to combat and cure bacterial infections: An ambitious and also a realistic applications?, Appl. Microb. Biotechnol., 2018, vol. 102, pp. 2563–2581.CrossRefGoogle Scholar
  78. 78.
    Majkowska-Skrobek, G., Latka, A., Berisio, R., Maciejewska, B., Squeglia, F., et al., Capsule-targeting depolymerase, derived from Klebsiella KP36 phage, as a tool for the development of anti-virulent strategy, Viruses, 2016, vol. 8, no. 12, p. E324.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Pan, Y.J., Lin, T.L., Lin, Y.T., Su, P.A., Chen, C.T., et al., Identification of capsular type of carbapenem-resistant Klebsiella pneumoniae strains by wzc sequencing and implications for capsule depolymerase treatment, Antimicrob. Agents Chemother., 2015, vol. 59, pp. 1038–1047.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Wasch, S., Hanifi-Modhaddam, P., Coleman, R., Mcsotti, M., Ryan, S., et al., Orally administered P22 phage tailspike protein reduces salmonella colonization in chickens: Prospects of a novel therapy against bacterial infections, PLoS One, 2010, vol. 5, p. e13904.CrossRefGoogle Scholar
  81. 81.
    Glonti, T., Chanishvili, N., and Taylor, P.W., Bacteriophage-derived enzyme that depolymerizes the alginic acid capsule associated with cystic fibrosis isolates of Pseudomonas aeruginosa, J. Appl. Microbiol., 2010, vol. 108, pp. 695–702.PubMedCrossRefGoogle Scholar
  82. 82.
    Bansal, S., Soni, S.K., Harjai, K., and Chhibber, S., Aeromonas punctata derived depolymerase that disrupts the integrity of Klebsiella pneumoniae capsule: Optimization of depolymerase production, J. Basic Microbiol., 2014, vol. 54, pp. 711–720.PubMedCrossRefGoogle Scholar
  83. 83.
    Chai, Z., Wang, J., Too, S., and Mou, H., Application of bacterial-borne enzyme combined with chlorine dioxide on controlling bacterial biofilm, LWT–Food Sci. Technol., 2014, vol. 59, pp. 1159–1165.CrossRefGoogle Scholar

Copyright information

© Allerton Press, Inc. 2019

Authors and Affiliations

  • T. S. Ilyina
    • 1
  • E. R. Tolordava
    • 1
  • Yu. M. Romanova
    • 1
    • 2
    Email author
  1. 1.Gamaleya National Research Center of Epidemiology and Microbiology of the Ministry of Health of the Russian FederationMoscowRussia
  2. 2.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University)MoscowRussia

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