Review Article

Bacteriophage Therapy as An Alternative to Antibiotics: A Dead End or A Solution?

Abstract

Antibiotic resistance has been around for years and could lead to a serious crisis in the near future. If the problem of antibiotic resistance is not solved, it is estimated that the increase in antimicrobial resistance would kill 10 million people a year by 2050 (more than the number of cancer deaths) and cost the world economy about 100 trillion USD, which will require immediate development of alternative treatments (1) (2). This problem prompted scientists to find a solution; one of these strategies is the use of bacteriophages as an alternative to antibiotics. In this review article, I will first focus on bacteriophages from various aspects and then, by analyzing the available information, I will try to answer the following questions:

  1. Given the meager standard clinical data and characteristics of bacteriophages, is bacteriophage therapy a safe and reliable method?
  2. Given the short time left before the antibiotic resistance crisis, is it cost-effective to invest in bacteriophage?
  3. Are bacteriophages a double-edged sword? (Besides being used to treat bacterial diseases in the future, do bacteriophages have the potential to become a human virus in the future?)
1. Romero-Calle D, Guimarães Benevides R, Góes-Neto A, Billington C. Bacteriophages as alternatives to antibiotics in clinical care. Antibiotics. 2019,4;8(3):138.
2. Huys I, Pirnay JP, Lavigne R, Jennes S, De Vos D, Casteels M, et al. Paving a regulatory pathway for phage therapy: Europe should muster the resources to financially, technically and legally support the introduction of phage therapy. EMBO Rep. . 2013 Nov;14(11):951-4.
3. Kwiatek M, Parasion S, Nakonieczna A. Therapeutic bacteriophages as a rescue treatment for drug‐resistant infections–an in vivo studies overview. J. Appl. Microbiol. . 2020 Apr;128(4):985-1002.
4. Harper DR, Parracho HM, Walker J, Sharp R, Hughes G, Werthén M, et al. Bacteriophages and biofilms. Antibiotics. 2014 Jun 25;3(3):270-84.
5. Malik DJ, Sokolov IJ, Vinner GK, Mancuso F, Cinquerrui S, Vladisavljevic GT, et al. Formulation, stabilisation and encapsulation of bacteriophage for phage therapy. Adv. Colloid Interface Sci. . 2017 Nov 1;249:100-33.
6. Ross A, Ward S, Hyman P. More is better: selecting for broad host range bacteriophages. Front. Microbiol. . 2016 Sep 8;7:1352.
7. Forde A, Hill C. Phages of life–the path to pharma. Br. J. Pharmacol.. 2018 Feb;175(3):412-8.
8. Jończyk E, Kłak M, Międzybrodzki R, Górski A. The influence of external factors on bacteriophages. Folia Microbiol. (Praha). 2011 May;56(3):191-200.
9. Nikolich MP, Filippov AA. Bacteriophage therapy: developments and directions. Antibiotics. 2020 Mar 24;9(3):135.
10. Górski A, Jończyk-Matysiak E, Międzybrodzki R, Weber-Dąbrowska B, Łusiak-Szelachowska M, Bagińska N, et al. Phage therapy: beyond antibacterial action. Front. Med. . 2018 May 23;5:146.
11. Brown-Jaque M, Muniesa M, Navarro F. Bacteriophages in clinical samples can interfere with microbiological diagnostic tools. Sci. Rep. . 2016 Sep 9;6(1):1-8.
12. Malki K, Sible E, Cooper A, Garretto A, Bruder K, Watkins SC, et al. Seven bacteriophages isolated from the female urinary microbiota. Genome Announc. . 2016 Nov 23;4(6):e01003-16.
13. De Vlaminck I, Khush KK, Strehl C, Kohli B, Luikart H, Neff NF, et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell. 2013 Nov 21;155(5):1178-87.
14. Kowarsky M, Camunas-Soler J, Kertesz M, De Vlaminck I, Koh W, Pan W, et al. Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA. PNAS. 2017 Sep 5;114(36):9623-8.
15. Thannesberger J, Hellinger HJ, Klymiuk I, Kastner MT, Rieder FJ, Schneider M, et al. Viruses comprise an extensive pool of mobile genetic elements in eukaryote cell cultures and human clinical samples. FASEB J. . 2017 May;31(5):1987-2000.
16. Górski A, Ważna E, Dąbrowska BW, Dąbrowska K, Świtała-Jeleń K, Międzybrodzki R. Bacteriophage translocation. FEMS Immunol. Med. Microbiol. . 2006 Apr 1;46(3):313-9.
17. Barr JJ. A bacteriophages journey through the human body. Immunol. Rev. . 2017 Sep;279(1):106-22.
18. Nguyen S, Baker K, Padman BS, Patwa R, Dunstan RA, Weston TA, et al. Bacteriophage transcytosis provides a mechanism to cross epithelial cell layers. MBio. 2017 Nov 21;8(6):e01874-17.
19. Hendrix RW. Bacteriophages: evolution of the majority. Theor. Popul. Biol. . 2002 Jun 1;61(4):471-80.
20. Hanlon GW. Bacteriophages: an appraisal of their role in the treatment of bacterial infections. Int. J. Antimicrob. Agents. 2007 Aug 1;30(2):118-28.
21. Prigent M, Leroy M, Confalonieri F, Dutertre M, DuBow MS. A diversity of bacteriophage forms and genomes can be isolated from the surface sands of the Sahara Desert. Extremophiles. 2005 Aug;9(4):289-96.
22. Lin L, Hong W, Ji X, Han J, Huang L, Wei Y. Isolation and characterization of an extremely long tail Thermus bacteriophage from Tengchong hot springs in China. J. Basic Microbiol.. 2010 Oct;50(5):452-6.
23. Breitbart M, Wegley L, Leeds S, Schoenfeld T, Rohwer F. Phage community dynamics in hot springs. Appl. Environ. Microbiol. . 2004 Mar;70(3):1633-40.
24. Wichels A, Biel SS, Gelderblom HR, Brinkhoff T, Muyzer G, Schütt C. Bacteriophage diversity in the North Sea. Appl. Environ. Microbiol. . 1998 Nov 1;64(11):4128-33.
25. Säwström C, Lisle J, Anesio AM, Priscu JC, Laybourn-Parry J. Bacteriophage in polar inland waters. Extremophiles. 2008 Mar;12(2):167-75.
26. Lucena F, Ribas F, Duran AE, Skraber S, Gantzer C, Campos C, et al. Occurrence of bacterial indicators and bacteriophages infecting enteric bacteria in groundwater in different geographical areas. J. Appl. Microbiol. . 2006 Jul;101(1):96-102.
27. Yoon SS, Barrangou-Poueys R, Breidt Jr F, Klaenhammer TR, Fleming HP. Isolation and characterization of bacteriophages from fermenting sauerkraut. Appl. Environ. Microbiol. . 2002 Feb;68(2):973-6.
28. Davis CR, Silveira NF, Fleet GH. Occurrence and properties of bacteriophages of Leuconostoc oenos in Australian wines. Appl. Environ. Microbiol. . 1985 Oct;50(4):872-6.
29. Kumari S, Harjai K, Chhibber S. Isolation and characterization of Klebsiella pneumoniae specific bacteriophages from sewage samples. Folia Microbiol. (Praha). 2010 May;55(3):221-7.
30. Tartera CA, Jofre JU. Bacteriophages active against Bacteroides fragilis in sewage-polluted waters. Appl. Environ. Microbiol. . 1987 Jul;53(7):1632-7.
31. Penesyan A, Paulsen IT, Kjelleberg S, Gillings MR. Three faces of biofilms: A microbial lifestyle, a nascent multicellular organism, and an incubator for diversity. NPJ Biofilms Microbiomes. 2021 Nov 10;7(1):1-9.
32. NIH. (2002). Research on microbial biofilms. Report No. PA-03-047 (National Institutes of Health, Bethesda, 2002).
33. Penesyan A, Gillings M, Paulsen IT. Antibiotic discovery: combatting bacterial resistance in cells and in biofilm communities. Molecules. 2015 Mar 24;20(4):5286-98.
34. Boudarel H, Mathias JD, Blaysat B, Grédiac M. Towards standardized mechanical characterization of microbial biofilms: analysis and critical review. NPJ Biofilms Microbiomes. 2018 Aug 20;4(1):1-5.
35. Olivares E, Badel-Berchoux S, Provot C, Prévost G, Bernardi T, Jehl F. Clinical impact of antibiotics for the treatment of Pseudomonas aeruginosa biofilm infections. Front. Microbiol. . 2020 Jan 9;10:2894.
36. Paraje MG. Antimicrobial resistance in biofilms. Science against microbial pathogens: communicating current research and technological advances. 2011;2:736-4.
37. Hentzer M, Teitzel GM, Balzer GJ, Heydorn A, Molin S, Givskov M, et al. Alginate overproduction affects Pseudomonas aeruginosa biofilm structure and function. JB. 2001 Sep 15;183(18):5395-401.
38. Drulis-Kawa Z, Maciejewska B. “Bacteriophages and Biofilms”. Viruses. 2021 Feb 8;13(2):257.
39. Doub JB. Bacteriophage therapy for clinical biofilm infections: parameters that influence treatment protocols and current treatment approaches. Antibiotics. 2020 Nov 12;9(11):799.
40. Chaudhry WN, Concepcion-Acevedo J, Park T, Andleeb S, Bull JJ, Levin BR. Synergy and order effects of antibiotics and phages in killing Pseudomonas aeruginosa biofilms. PLoS One. 2017 Jan 11;12(1):e0168615.
41. Mendes JJ, Leandro C, Corte‐Real S, Barbosa R, Cavaco‐Silva P, Melo‐Cristino J, et al. Wound healing potential of topical bacteriophage therapy on diabetic cutaneous wounds. Wound Repair Regen. 2013 Jul;21(4):595-603.
42. Kaur S, Harjai K, Chhibber S. Bacteriophage mediated killing of Staphylococcus aureus in vitro on orthopaedic K wires in presence of linezolid prevents implant colonization. PLoS One. 2014 Mar 3;9(3):e90411.
43. Morris JL, Letson HL, Elliott L, Grant AL, Wilkinson M, Hazratwala K, et al. Evaluation of bacteriophage as an adjunct therapy for treatment of peri-prosthetic joint infection caused by Staphylococcus aureus. PLoS One. 2019 Dec 26;14(12):e0226574.
44. Cobb LH, Park J, Swanson EA, Beard MC, McCabe EM, Rourke AS, et al. CRISPR-Cas9 modified bacteriophage for treatment of Staphylococcus aureus induced osteomyelitis and soft tissue infection. PLoS One. 2019 Nov 22;14(11):e0220421.
45. Ibrahim OM, Sarhan SR, Salih SI. Activity of isolated staphylococcal bacteriophage in treatment of experimentally induced chronic osteomyelitis in rabbits. Adv. Anim. Vet. Sci. 2016;4(11):593-603.
46. Kishor C, Mishra RR, Saraf SK, Kumar M, Srivastav AK, Nath G. Phage therapy of staphylococcal chronic osteomyelitis in experimental animal model. IJMR. 2016 Jan;143(1):87.
47. Wroe JA, Johnson CT, García AJ. Bacteriophage delivering hydrogels reduce biofilm formation in vitro and infection in vivo. J Biomed Mater Res A. 2020 Jan;108(1):39-49.
48. Międzybrodzki R, Borysowski J, Weber-Dąbrowska B, Fortuna W, Letkiewicz S, Szufnarowski K, et al. Clinical aspects of phage therapy. Adv. Virus Res. . 2012 Jan 1;83:73-121.
49. Akturk E, Oliveira H, Santos SB, Costa S, Kuyumcu S, Melo LD, et al. Synergistic action of phage and antibiotics: parameters to enhance the killing efficacy against mono and dual-species biofilms. Antibiotics. 2019 Jul 25;8(3):103.
50. Wienhold SM, Lienau J, Witzenrath M. Towards inhaled phage therapy in Western Europe. Viruses. 2019 Mar 23;11(3):295.
51. Abedon ST. Ecology of anti-biofilm agents I: antibiotics versus bacteriophages. Pharmaceuticals. 2015 Sep 9;8(3):525-58.
52. Abedon ST. Bacteriophage exploitation of bacterial biofilms: phage preference for less mature targets?. FEMS Microbiol. Lett. . 2016 Feb 1;363(3):fnv246.
53. Lood R, Ertürk G, Mattiasson B. Revisiting antibiotic resistance spreading in wastewater treatment plants–bacteriophages as a much neglected potential transmission vehicle. Front. Microbiol. . 2017 Nov 21;8:2298.
54. Schlüter A, Szczepanowski R, Pühler A, Top EM. Genomics of IncP-1 antibiotic resistance plasmids isolated from wastewater treatment plants provides evidence for a widely accessible drug resistance gene pool. FEMS Microbiol. Rev. . 2007 Jul 1;31(4):449-77.
55. Bouki C, Venieri D, Diamadopoulos E. Detection and fate of antibiotic resistant bacteria in wastewater treatment plants: a review. Ecotoxicol. Environ. Saf. . 2013 May 1;91:1-9.
56. Gatica J, Cytryn E. Impact of treated wastewater irrigation on antibiotic resistance in the soil microbiome. ESPR. 2013 Jun;20(6):3529-38.
57. Rizzo L, Manaia C, Merlin C, Schwartz T, Dagot C, Ploy MC, et al. Urban wastewater treatment plants as hotspots for antibiotic resistant bacteria and genes spread into the environment: a review. Sci. Total Environ. . 2013 Mar 1;447:345-60.
58. Withey S, Cartmell E, Avery LM, Stephenson T. Bacteriophages—potential for application in wastewater treatment processes. Sci. Total Environ. . 2005 Mar 1;339(1-3):1-8.
59. Muniesa M, Imamovic L, Jofre J. Bacteriophages and genetic mobilization in sewage and faecally polluted environments. Microb. Biotechnol. . 2011 Nov;4(6):725-34.
60. Muniesa M, Colomer-Lluch M, Jofre J. Potential impact of environmental bacteriophages in spreading antibiotic resistance genes. Future Microbiol. . 2013 Jun;8(6):739-51.
61. Balcazar JL. Bacteriophages as vehicles for antibiotic resistance genes in the environment. PLoS Pathog. . 2014 Jul 31;10(7):e1004219.
62. Balcázar JL. How do bacteriophages promote antibiotic resistance in the environment?. CMI. 2018 May 1;24(5):447-9.
63. Frost LS, Leplae R, Summers AO, Toussaint A. Mobile genetic elements: the agents of open source evolution. Nat. Rev. Microbiol. . 2005 Sep;3(9):722-32.
64. Courvalin P. Transfer of antibiotic resistance genes between gram-positive and gram-negative bacteria. Antimicrob. Agents Chemother. . 1994 Jul;38(7):1447-51.
65. Brown-Jaque M, Rodriguez Oyarzun L, Cornejo-Sánchez T, Martín-Gómez MT, Gartner S, De Gracia J, et al. Detection of bacteriophage particles containing antibiotic resistance genes in the sputum of cystic fibrosis patients. Front. Microbiol. . 2018 May 1;9:856.
66. Colomer-Lluch M, Imamovic L, Jofre J, Muniesa M. Bacteriophages carrying antibiotic resistance genes in fecal waste from cattle, pigs, and poultry. Antimicrob. Agents Chemother. . 2011 Oct;55(10):4908-11.
67. Mitsuhashi S, Harada K, Hashimoto H, Kameda M, Suzuki M. Combination of two types of transmissible drug-resistance factors in a host bacterium. J. Bacteriol. . 1962 Jul;84(1):9-16.
68. Hirota Y, Fujii T, Nishimura Y. Loss and repair of conjugal fertility and infectivity of the resistance factor and sex factor in Escherichia coli. J. Bacteriol. . 1966 Mar;91(3):1298-304.
69. Hardiman CA, Weingarten RA, Conlan S, Khil P, Dekker JP, Mathers AJ, et al. Horizontal transfer of carbapenemase-encoding plasmids and comparison with hospital epidemiology data. Antimicrob. Agents Chemother. . 2016 Aug 1;60(8):4910-9.
70. Chen L, Chavda KD, Melano RG, Hong T, Rojtman AD, Jacobs MR, et al. Molecular survey of the dissemination of two bla KPC-harboring IncFIA plasmids in New Jersey and New York hospitals. Antimicrob. Agents Chemother. . 2014 Apr;58(4):2289-94.
71. Canchaya C, Fournous G, Brüssow H. The impact of prophages on bacterial chromosomes. Mol. Microbiol. . 2004 Jul;53(1):9-18.
72. Brabban AD, Hite E, Callaway TR. Evolution of foodborne pathogens via temperate bacteriophage-mediated gene transfer. Foodborne Pathog. Dis. . 2005 Dec 1;2(4):287-303.
73. Koskella B, Meaden S. Understanding bacteriophage specificity in natural microbial communities. Viruses. 2013 Mar 11;5(3):806-23.
74. Loc-Carrillo C, Abedon ST. Pros and cons of phage therapy. Bacteriophage. 2011 Mar 1;1(2):111-4.
75. Yang Y, Shen W, Zhong Q, Chen Q, He X, Baker JL, et al. Development of a bacteriophage cocktail to constrain the emergence of phage-resistant Pseudomonas aeruginosa. Front. Microbiol. . 2020 Mar 4;11:327.
76. Chan BK, Abedon ST, Loc-Carrillo C. Phage cocktails and the future of phage therapy. Future Microbiol. . 2013 Jun;8(6):769-83.
77. Principi N, Silvestri E, Esposito S. Advantages and limitations of bacteriophages for the treatment of bacterial infections. Front. Pharmacol. . 2019 May 8;10:513.
78. Iszatt JJ, Larcombe AN, Chan HK, Stick SM, Garratt LW, Kicic A. Phage therapy for multi-drug resistant respiratory tract infections. Viruses. 2021 Sep 11;13(9):1809.
79. Breitbart M, Haynes M, Kelley S, Angly F, Edwards RA, Felts B, et al. Viral diversity and dynamics in an infant gut. Res. Microbiol. . 2008 Jun 1;159(5):367-73.
80. Manrique P, Bolduc B, Walk ST, van der Oost J, de Vos WM, Young MJ. Healthy human gut phageome. PNAS. 2016 Sep 13;113(37):10400-5.
81. Dąbrowska K, Miernikiewicz P, Piotrowicz A, Hodyra K, Owczarek B, Lecion D, et al. Immunogenicity studies of proteins forming the T4 phage head surface. J. Virol. . 2014 Nov 1;88(21):12551-7.
82. Van Belleghem JD, Dąbrowska K, Vaneechoutte M, Barr JJ, Bollyky PL. Interactions between bacteriophage, bacteria, and the mammalian immune system. Viruses. 2018 Dec 25;11(1):10.
83. Kutter E, De Vos D, Gvasalia G, Alavidze Z, Gogokhia L, Kuhl S, et al. Phage therapy in clinical practice: treatment of human infections. Curr. Pharm. Biotechnol. . 2010 Jan 1;11(1):69-86.
84. Górski A, Międzybrodzki R, Borysowski J, Dąbrowska K, Wierzbicki P, Ohams M, et al. Phage as a modulator of immune responses: practical implications for phage therapy. Adv. Virus Res. . 2012 Jan 1;83:41-71.
85. Górski A, Jończyk-Matysiak E, Łusiak-Szelachowska M, Międzybrodzki R, Weber-Dąbrowska B, Borysowski J. The potential of phage therapy in sepsis. Front. Immunol. . 2017 Dec 11;8:1783.
86. Roach DR, Leung CY, Henry M, Morello E, Singh D, Di Santo JP, et al. Synergy between the host immune system and bacteriophage is essential for successful phage therapy against an acute respiratory pathogen. Cell Host Microbe. 2017 Jul 12;22(1):38-47.
87. Gogokhia L, Buhrke K, Bell R, Hoffman B, Brown DG, Hanke-Gogokhia C, et al. Expansion of bacteriophages is linked to aggravated intestinal inflammation and colitis. Cell Host Microbe. 2019 Feb 13;25(2):285-99.
88. Łusiak-Szelachowska M, Żaczek M, Weber-Dąbrowska B, Międzybrodzki R, Kłak M, Fortuna W, et al. Phage neutralization by sera of patients receiving phage therapy. Viral Immunol. . 2014 Aug 1;27(6):295-304.
89. Sulakvelidze A, Alavidze Z, Morris Jr JG. Bacteriophage therapy. Antimicrob. Agents Chemother. . 2001 Mar 1;45(3):649-59.
90. Popescu M, Van Belleghem JD, Khosravi A, Bollyky PL. Bacteriophages and the immune system. Annu. Rev. Virol. 2021 Sep 29;8:415-35.
91. Hoyles L, McCartney AL, Neve H, Gibson GR, Sanderson JD, Heller KJ, et al. Characterization of virus-like particles associated with the human faecal and caecal microbiota. Res. Microbiol. . 2014 Dec 1;165(10):803-12.
92. Broecker F, Russo G, Klumpp J, Moelling K. Stable core virome despite variable microbiome after fecal transfer. Gut Microbes. 2017 May 4;8(3):214-20.
93. Shkoporov AN, Clooney AG, Sutton TD, Ryan FJ, Daly KM, Nolan JA, et al. The human gut virome is highly diverse, stable, and individual specific. Cell Host Microbe. 2019 Oct 9;26(4):527-41.
94. Ogilvie LA, Jones BV. The human gut virome: a multifaceted majority. Front. Microbiol. . 2015:918.
95. Zuo T, Wong SH, Lam K, Lui R, Cheung K, Tang W, et al. Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome. Gut. 2018 Apr 1;67(4):634-43.
96. Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC, et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell. 2015 Jan 29;160(3):447-60.
97. Ma Y, You X, Mai G, Tokuyasu T, Liu C. A human gut phage catalog correlates the gut phageome with type 2 diabetes. Microbiome. 2018 Dec;6(1):1-2.
98. Gregory AC, Sullivan MB, Segal LN, Keller BC. Smoking is associated with quantifiable differences in the human lung DNA virome and metabolome. Respir. Res. . 2018 Dec;19(1):1-3.
99. Weinbauer MG. Ecology of prokaryotic viruses. FEMS Microbiol. Rev. . 2004 May 1;28(2):127-81.
100. Brüssow H, Canchaya C, Hardt WD. Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. MMBR. 2004 Sep 1;68(3):560-602.
101. Waldor MK, Mekalanos JJ. Lysogenic conversion by a filamentous phage encoding cholera toxin. Science. 1996 Jun 28;272(5270):1910-4.
102. Schmitt MP, Twiddy EM, Holmes RK. Purification and characterization of the diphtheria toxin repressor. PNAS. 1992 Aug 15;89(16):7576-80.
103. Schmitt MP, Holmes RK. Iron-dependent regulation of diphtheria toxin and siderophore expression by the cloned Corynebacterium diphtheriae repressor gene dtxR in C. diphtheriae C7 strains. Infect. Immun. . 1991 Jun;59(6):1899-904.
104. Boyd J, Oza MN, Murphy JR. Molecular cloning and DNA sequence analysis of a diphtheria tox iron-dependent regulatory element (dtxR) from Corynebacterium diphtheriae. PNAS. 1990 Aug;87(15):5968-72.
105. Voelker LL, Dybvig K. Sequence analysis of the Mycoplasma arthritidis bacteriophage MAV1 genome identifies the putative virulence factor. Gene. 1999 Jun 11;233(1-2):101-7.
106. Barr JJ, Auro R, Furlan M, Whiteson KL, Erb ML, Pogliano J, et al. Bacteriophage adhering to mucus provide a non–host-derived immunity. PNAS. 2013 Jun 25;110(26):10771-6.
107. Fraser JS, Yu Z, Maxwell KL, Davidson AR. Ig-like domains on bacteriophages: a tale of promiscuity and deceit. J. Mol. Biol. . 2006 Jun 2;359(2):496-507.
108. Bateman A, Eddy SR, Mesyanzhinov VV. A member of the immunoglobulin superfamily in bacteriophage T4. Virus Genes. 1997 Mar;14(2):163-5.
109. Almeida GM, Laanto E, Ashrafi R, Sundberg LR. Bacteriophage adherence to mucus mediates preventive protection against pathogenic bacteria. MBio. 2019 Nov 19;10(6):e01984-19.
110. Barr JJ, Auro R, Sam-Soon N, Kassegne S, Peters G, Bonilla N, et al. Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters. PNAS. 2015 Nov 3;112(44):13675-80.
111. Yang JY, Kim MS, Kim E, Cheon JH, Lee YS, Kim Y, et al. Enteric viruses ameliorate gut inflammation via toll-like receptor 3 and toll-like receptor 7-mediated interferon-β production. Immunity. 2016 Apr 19;44(4):889-900.
112. Sechter I, Touitou E, Donbrow M. The influence of a non-ionic surfactant on rectal absorption of virus particles. Arch. Virol. . 1989 Mar;106(1):141-3.
113. Hoffmann M. Animal Experiments on Mucosal Passage and Absorption Viraemia of T3 Phages after Oral, Trachéal and Rectal Administration. Zent.bl. Bakteriol. Parasitenkd. Infekt.krankh. Hyg. . 1965;198(4):371-90.
114. Keller R, Engley Jr FB. Fate of bacteriophage particles introduced into mice by various routes. Proc. Soc. Exp. Biol. Med. . 1958 Jul;98(3):577-80.
115. Geier MR, Trigg ME, Merril CR. Fate of bacteriophage lambda in non-immune germ-free mice. Nature. 1973 Nov;246(5430):221-3.
116. Inchley CJ. The activity of mouse Kupffer cells following intravenous injection of T4 bacteriophage. Clin. Exp. Immunol. . 1969 Aug;5(2):173.
117. Smith HW, Huggins MB. Successful treatment of experimental Escherichia coli infections in mice using phage: its general superiority over antibiotics. Microbiology. 1982 Feb 1;128(2):307-18.
118. Reynaud A, Cloastre L, Bernard J, Laveran H, Ackermann HW, Licois D, et al. Characteristics and diffusion in the rabbit of a phage for Escherichia coli 0103. Attempts to use this phage for therapy. Vet. Microbiol. . 1992 Feb 1;30(2-3):203-12.
119. Żaczek M, Górski A, Skaradzińska A, Łusiak-Szelachowska M, Weber-Dąbrowska B. Phage penetration of eukaryotic cells: practical implications. Future Virol. . 2019 Nov;14(11):745-60.
120. Podlacha M, Grabowski Ł, Kosznik-Kawśnicka K, Zdrojewska K, Stasiłojć M, Węgrzyn G, et al. Interactions of bacteriophages with animal and human organisms—safety issues in the light of phage therapy. Int. J. Mol. Sci. . 2021 Aug 19;22(16):8937.
121. Kim A, Shin TH, Shin SM, Pham CD, Choi DK, Kwon MH, et al. Cellular internalization mechanism and intracellular trafficking of filamentous M13 phages displaying a cell-penetrating transbody and TAT peptide. PLoS One. 2012 Dec 14;7(12):e51813.
122. Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat. Med. . 2019 May;25(5):730-3.
123. Manickan E, Karem KL, Rouse BT. DNA Vaccines–A Modern Gimmick or a Boon to Vaccinology?. Crit. Rev. Immunol. . 2017;37(2-6).
124. Bodner K, Melkonian AL, Covert MW. The enemy of my enemy: New insights regarding bacteriophage–mammalian cell interactions. Trends Microbiol. . 2021 Jun 1;29(6):528-41.
125. Hess KL, Jewell CM. Phage display as a tool for vaccine and immunotherapy development. BioTM. 2020 Jan;5(1):e10142.
126. Paludan SR, Bowie AG. Immune sensing of DNA. Immunity. 2013 May 23;38(5):870-80.
127. Hashiguchi S, Yamaguchi Y, Takeuchi O, Akira S, Sugimura K. Immunological basis of M13 phage vaccine: Regulation under MyD88 and TLR9 signaling. BBRC. 2010 Nov 5;402(1):19-22.
128. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front. immunol. . 2014:461.
129. Rutz M, Metzger J, Gellert T, Luppa P, Lipford GB, Wagner H, et al. Toll‐like receptor 9 binds single‐stranded CpG‐DNA in a sequence‐and pH‐dependent manner. Eur. J. Immunol. . 2004 Sep;34(9):2541-50.
130. Sweere JM, Van Belleghem JD, Ishak H, Bach MS, Popescu M, Sunkari V, et al. Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection. Science. 2019 Mar 29;363(6434):eaat9691.
131. Przerwa A, Zimecki M, Świtała-Jeleń K, Dąbrowska K, Krawczyk E, Łuczak M, et al. Effects of bacteriophages on free radical production and phagocytic functions. Med. Microbiol. Immunol. . 2006 Sep;195(3):143-50.
132. Jahn MT, Arkhipova K, Markert SM, Stigloher C, Lachnit T, Pita L, et al. A phage protein aids bacterial symbionts in eukaryote immune evasion. Cell Host Microbe. 2019 Oct 9;26(4):542-50.
133. Majewska J, Kaźmierczak Z, Lahutta K, Lecion D, Szymczak A, Miernikiewicz P, et al. Induction of phage-specific antibodies by two therapeutic staphylococcal bacteriophages administered per os. Front. immunol. . 2019 Nov 14;10:2607.
134. Kucharewicz-Krukowska A, Slopek S. Immunogenic effect of bacteriophage in patients subjected to phage therapy. AITE. 1987 Jan 1;35(5):553-61.
135. Krag DN, Shukla GS, Shen GP, Pero S, Ashikaga T, Fuller S, et al. Selection of tumor-binding ligands in cancer patients with phage display libraries. Cancer Res. . 2006 Aug 1;66(15):7724-33.
136. Dabrowska K, Zembala M, Boratynski J, Switala-Jelen K, Wietrzyk J, Opolski A, et al. Hoc protein regulates the biological effects of T4 phage in mammals. Arch. Microbiol. . 2007 Jun;187(6):489-98.
137. Dabrowska K, Opolski A, Wietrzyk J, Switala-Jelen K, Godlewska J, Boratynski J, et al. Anticancer activity of bacteriophage T4 and its mutant HAP1 in mouse experimental tumour models. Anticancer Res. . 2004 Nov 1;24(6):3991-6.
138. Hodyra‐Stefaniak K, Lahutta K, Majewska J, Kaźmierczak Z, Lecion D, Harhala M, et al. Bacteriophages engineered to display foreign peptides may become short‐circulating phages. Microb. Biotechnol. . 2019 Jul;12(4):730-41.
139. Basu R, Zhai L, Contreras A, Tumban E. Immunization with phage virus-like particles displaying Zika virus potential B-cell epitopes neutralizes Zika virus infection of monkey kidney cells. Vaccine. 2018 Feb 28;36(10):1256-64.
140. Wang L, Gao J, Lan X, Zhao H, Shang X, Tian F, et al. Identification of combined T-cell and B-cell reactive Echinococcus granulosus 95 antigens for the potential development of a multi-epitope vaccine. Ann. Transl. Med. . 2019 Nov;7(22).
141. Carvalho GB, Costa LE, Lage DP, Ramos FF, Santos TT, Ribeiro PA, et al. High-through identification of T cell-specific phage-exposed mimotopes using PBMCs from tegumentary leishmaniasis patients and their use as vaccine candidates against Leishmania amazonensis infection. Parasitology. 2019 Mar;146(3):322-32.
142. Tao P, Mahalingam M, Kirtley ML, van Lier CJ, Sha J, Yeager LA, et al. Mutated and bacteriophage T4 nanoparticle arrayed F1-V immunogens from Yersinia pestis as next generation plague vaccines. PLoS Pathog. . 2013 Jul 11;9(7):e1003495.
143. Iwagami Y, Casulli S, Nagaoka K, Kim M, Carlson RI, Ogawa K, et al. Lambda phage-based vaccine induces antitumor immunity in hepatocellular carcinoma. Heliyon. 2017 Sep 1;3(9):e00407.
144. Kumar B, Mishra AK, Prakash C, Priyadarshini A, Rawat M. Immunization with Salmonella Abortusequi phage lysate protects guinea pig against the virulent challenge of SAE-742. Biologicals. 2018 Nov 1;56:24-8.
145. Dufour N, Henry M, Ricard JD, Debarbieux L. Commentary: morphologically distinct Escherichia coli bacteriophages differ in their efficacy and ability to stimulate cytokine release in vitro. Front. Microbiol. . 2016 Jun 28;7:1029.
146. Azam AH, Tan XE, Veeranarayanan S, Kiga K, Cui L. Bacteriophage Technology and Modern Medicine. Antibiotics. 2021 Aug 18;10(8):999.
147. Chatterjee A, Duerkop BA. Beyond bacteria: bacteriophage-eukaryotic host interactions reveal emerging paradigms of health and disease. Front. Microbiol. . 2018 Jun 27;9:1394.
148. Duerkop BA, Hooper LV. Resident viruses and their interactions with the immune system. Nat. Immunol. . 2013 Jul;14(7):654-9.
149. Lehti TA, Pajunen MI, Skog MS, Finne J. Internalization of a polysialic acid-binding Escherichia coli bacteriophage into eukaryotic neuroblastoma cells. Nat. Commun. . 2017 Dec 4;8(1):1-2.
150. Rosenwald AG, Murray B, Toth T, Madupu R, Kyrillos A, Arora G. Evidence for horizontal gene transfer between Chlamydophila pneumoniae and Chlamydia phage. Bacteriophage. 2014 Dec 15;4(4):e965076.
151. Bordenstein SR, Bordenstein SR. Eukaryotic association module in phage WO genomes from Wolbachia. Nat. Commun. . 2016 Oct 11;7(1):1-0.
152. Blanco-Picazo P, Fernández-Orth D, Brown-Jaque M, Miró E, Espinal P, Rodríguez-Rubio L, et al. Unravelling the consequences of the bacteriophages in human samples. Sci. Rep. . 2020 Apr 21;10(1):1-0.
153. Porayath C, Salim A, Veedu AP, Babu P, Nair B, Madhavan A, et al. Characterization of the bacteriophages binding to human matrix molecules. Int. J. Biol. Macromol. . 2018 Apr 15;110:608-15.
154. Garcia P, Martinez B, Obeso JM, Rodriguez A. Bacteriophages and their application in food safety. Lett. Appl. Microbiol. . 2008 Dec;47(6):479-85.
155. Chen Y, Batra H, Dong J, Chen C, Rao VB, Tao P. Genetic engineering of bacteriophages against infectious diseases. Front. Microbiol. . 2019 May 3;10:954.
156. Tetz G, Tetz V. Bacteriophages as new human viral pathogens. Microorganisms. 2018 Jun 16;6(2):54.
157. Mäntynen S, Sundberg LR, Oksanen HM, Poranen MM. Half a century of research on membrane-containing bacteriophages: bringing new concepts to modern virology. Viruses. 2019 Jan 18;11(1):76.
158. Spinelli S, Desmyter A, Verrips CT, de Haard HJ, Moineau S, Cambillau C. Lactococcal bacteriophage p2 receptor-binding protein structure suggests a common ancestor gene with bacterial and mammalian viruses. Nat. Struct. Mol. Biol. . 2006 Jan;13(1):85-9.
159. Hyman P. Phages for phage therapy: isolation, characterization, and host range breadth. Pharmaceuticals. 2019 Mar 11;12(1):35.
160. Duffy S, Burch CL, Turner PE. Evolution of host specificity drives reproductive isolation among RNA viruses. Evolution. 2007 Nov;61(11):2614-22.
161. Hyman P, Abedon ST. Bacteriophage host range and bacterial resistance. Adv. Appl. Microbiol. . 2010 Jan 1;70:217-48.
162. Gonzalez-Menendez E, Fernandez L, Gutierrez D, Rodriguez A, Martinez B, Garcia P. Comparative analysis of different preservation techniques for the storage of Staphylococcus phages aimed for the industrial development of phage-based antimicrobial products. PLoS One. 2018 Oct 11;13(10):e0205728.
163. Malik DJ, Resch G. Manufacturing, formulation and delivery issues for phage therapy to become a reality. Front. Microbiol. . 2020 Oct 8;11:584137.
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IssueVol 4, No 3 (2021) QRcode
SectionReview Article
DOI https://doi.org/10.18502/igj.v4i3.12114
Keywords
Bacteriophage Therapy Bacteriophage Resistance Antibiotic Resistance Biofilm Challenges of the Pharmaceutical Industry Microbiome

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1.
Rismanbaf A. Bacteriophage Therapy as An Alternative to Antibiotics: A Dead End or A Solution?. Immunol Genet J. 2021;4(3):138-154.