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

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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.

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Fig. 1.


  1. 1

    Ackermann, H.-W. and Prangishvilli, D., Prokaryote viruses studied by electron microscopy, Arch. Virol., 2012, vol. 157, pp. 1843–1849. PMID: 22752841.

  2. 2

    Lwoff, A., Lysogeny, Bacteriol. Rev., 1953, vol. 17, pp. 269–337. PMID 13105613.

  3. 3

    Adams, M.H., Bacteriophages, New York: Interscience Publ., 1959.

  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.

  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.

  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.

  7. 7

    Sulakvelidze, A., Alavidze, Z., and Morris, J.G., Jr., Bacteriophage therapy, Antimicrob. Agents Chemother., 2001, vol. 45, pp. 649–659.

  8. 8

    Chanishvili, N., A Literature Review of the Practical Application of Bacteriophage Research, Hauppauge, NY: Nova Science Publ., 2012.

  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.

  10. 10

    WHO (World Health Organization). Antimicrobial Resistance: Global Report on Surveillance, Geneva: World Health Organization, 2014.

  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.

  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.

  13. 13

    Abedon, S.T., Ecology of anti-biofilm agents I: Antibiotics versus bacteriophages, Pharmaceuticals (Basel), 2015, vol. 8, no. 3, pp. 525–558.

  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.

  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.

  16. 16

    Monteiro, R., Pires, D.P. and Costa, A.R., Phage Therapy: Going Temporate?, Trends Microbiol., 2019, vol. 27, no. 4, p. 378.

  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.

  18. 18

    Kutataladze, M., Experience of the Eliava Institute in bacteriophage therapy, Virol. Sin., 2015, vol. 30, pp. 80–81.

  19. 19

    Nilsson, A.S., Phage therapy–constraints and possibilities, Upsala J. Med. Sci., 2014, vol. 119, pp. 192–198.

  20. 20

    Labrie, J., Samson, J.E., and Moineau, S., Bacteriophage resistance mechanisms, Nat. Rev., 2010, vol. 8, pp. 317–327.

  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.

  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.

  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.

  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.

  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.

  26. 26

    Barrangou, R. and Oost, J., Bacteriophage exclusion, a new defense system, EMBO J., 2015, vol. 34, no. 2, pp. 134–135.

  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.

  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.

  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.

  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.

  31. 31

    Costerton, J.W., Introduction to biofilm, Int. J. Antimicrob. Agents, 1999, vol. 11, pp. 217–221.

  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.

  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.

  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.

  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.

  36. 36

    Abedon, S.T., Ecology of anti-biofilm agents I: Antibiotics versus bacteriophages, Pharmaceuticals (Basel), 2015, vol. 8, no. 3, pp. 525–558.

  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.

  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.

  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.

  40. 40

    Donlan, R.M., Preventing biofilms of clinically relevant organisms using bacteriophages, Trends Microbiol., 2009, vol. 17, pp. 66–72.

  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.

  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.

  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.

  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.

  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.

  46. 46

    Chan, B.K. and Abedon, S.T., Phage therapy pharmacology phage cocktails, Adv. Appl. Microbiol., 2012, vol. 78, pp. 1–23.

  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.

  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.

  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.

  50. 50

    Domingo-Calap, P. and Delgado-Martinez, J., Bacteriophages: Protagonists of a post-antibiotic era, Antibiotics, 2018, vol. 7, pp. 66–82.

  51. 51

    Torres-Barcelo, C. and Hochberg, M., Evolutionary rationale for phages as complements of antibiotics, Trends Microbiol., 2016, vol. 24, pp. 249–256.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  66. 66

    Fischetti, V.A., Bacteriophage lysins as effective antibacterials, Curr. Opin. Microbiol., 2008, vol. 11, pp. 393–400.

  67. 67

    Fischetti, V.A., Development of phage lysins as novel therapeutics: a historical perspective, Viruses, 2018, vol. 10, pp. 310–319.

  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.

  69. 69

    Gersmans, H., Criel, B., and Briers, Y., Synthetic biology of modular endolysins, Biotechnol. Adv., 2018, vol. 36, no. 3, pp. 624–640.

  70. 70

    Schmelchar, M., Donovan, D.M., and Loessner, M.J., Bacteriophage endolysins as novel antimicrobials, Future Microbiol., 2012, vol. 7, pp. 1147–1171.

  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.

  72. 72

    Roach, D.R. and Donovan, D.M., Antimicrobial bacteriophage-derived proteins and therapeutic applications, Bacteriophage, 2015, vol. 5, p. e1062590.

  73. 73

    Sao-Jose, C., Engineering of phage-derived enzymes: improving their potential as antimicrobials, Antibiotics, 2018, vol. 7, pp. 29–60.

  74. 74

    Yang, H., Yu, J., and Wei, H., Engineered bacteriophage lysins as novel anti-infectives, Front. Microbiol., 2014, vol. 5, p. 542.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

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Correspondence to Yu. M. Romanova.

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Translated by A. Panyushkina

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Ilyina, T.S., Tolordava, E.R. & Romanova, Y.M. A Look at Phage Therapy One Hundred Years After the Bacteriophages Discovery. Mol. Genet. Microbiol. Virol. 34, 149–158 (2019).

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