Modern Approaches to Bacteriophage Therapy of Infectious Diseases

The literature review includes works by domestic and foreign authors concerning the use of bacteriophages as an alternative method of therapy and prevention of the development of the inflammatory process in case of bacterial infections. The paper provides historical information about phage therapy. The properties of moderate and virulent bacteriophages, the main mechanisms of interaction of bacteriophage-based preparations with a bacterial cell are considered. Special attention is paid to the characteristic differences between the bacteriophage–bacterium interaction and the effects of antibiotics on microorganisms. The review contains information about the features of the surface binding of phages to microorganisms, anti-phage bacterial protection systems, as well as about the molecular and genetic antibacterial mechanisms of phage counteraction. The data on experimental and clinical studies of anti-phage cellular and humoral immunity and the effect of phages on cytokine production are presented. The literature review highlights the current state of the issue of the therapeutic and prophylactic significance of bacteriophages in relation to a wide range of bacterial infections. Special attention is paid to the literature concerning the study of information on the use of bacteriophages for the prevention and treatment of diseases caused by particularly dangerous microorganisms. The review contains information on the use of phage therapy as an alternative to antibiotics method to combat bacterial infection, both as an independent means of prevention and treatment, and in combination with antibiotic therapy. The data on the various mechanisms of synergy of bacteriophage preparations and antibiotics are presented. The review includes literature sources describing the occurrence of pathological reactions to the introduction of bacteriophages, as well as examples convincingly proving the effectiveness of an integrated approach strategy with the inclusion of phages in infectious disease control schemes, which should occupy a certain niche in the future.

1. Letarov A.V. [History of early bacteriophage research and the birth of basic concepts of virology]. Biokhimiya [Biochemistry]. 2020; 85(9):1189–212. DOI: 10.31857/S0320972520090031.

2. Gorshenin A.V. [The biography and scientific work of the Soviet microbiologist Z.V. Yermol’eva: historiographic characteristics of post-Soviet publications]. Samarsky Nauchny Vestnik [Samara Journal of Science]. 2020; 9(4):268–71. DOI: 10.17816/snv202094210.

3. Gaevskaya N.E., Makedonova L.D. [Use of bacteriophages in laboratory diagnostics of cholera]. Klinichekaya Laboratornaya Diagnostika. [Clinical Laboratory Diagnostics]. 2016; 61(12):849– 52. DOI: 10.18821/0869-2084-2016-61-12-849-852.

4. Rodrigues R.L., Denhardt D.T., editors. Vectors: A Survey of Molecular Cloning Vectors and Their Uses. Boston: Butterworth; 1988. 578 p.

5. Borgoyakova M.B., Il’ichev A.A. [Bacteriophages. Practical training in molecular virology]. Novosibirsk; 2013. 34 p. [Internet]. Available from: https://nsu.ru/xmlui/bitstream/handle/nsu/600/bactiriofag.pdf.

6. Topchy N.V., Toporkov A.S. [Bacteriophages in the treatment of acute intestinal infections]. Meditsinskiy Sovet [Medical Council]. 2015; (8):74–81. DOI: 10.21518/2079-701X-2015-8-74-81.

7. Il’ina T.S., Tolordava E.R., Romanova Yu.M. [Looking at phage therapy 100 years after the discovery of bacteriophages]. Molekulyarnaya Genetika, Mikrobiologiya i Virusologiya [Molecular Genetics, Microbiology and Virology]. 2019; 37(3):103–12. DOI: 10.17116/molgen201937031103.

8. PharmMedProm – [How viruses prevent epidemics and save lives in emergency situations: an expert view]. 08/30/2023. [Internet]. Available from: https://pharmmedprom.ru/articles/kak-virusi-predot-vraschayut-epidemii-i-spasayut-zhizni-v-usloviyah-chrezvichainihsituatsii-rasskazivaet-ekspert/.

9. Łusiak-Szelachowska M., Międzybrodzki R., Drulis-Kawa Z., Cater K., Knežević P., Winogradow C., Amaro K., Jończyk-Matysiak E., Weber-Dąbrowska B., Rękas J., Górski A. Bacteriophages and antibiotic interactions in clinical practice: what we have learned so far. J. Biomed. Sci. 2022; 29(1):23. DOI: 10.1186/s12929-022-00806-1.

10. Nir-Paz R., Gelman D., Khouri A., Sisson B.M., Fackler J., Alkalay-Oren S., Khalifa L., Rimon A., Yerushalmy O., Bader R., Amit S., Coppenhagen-Glazer S., Henry M., Quinones J., Malagon F., Biswas B., Moses A.E., Merril G., Schooley R.T., Brownstein M.J., Weil Y.A., Hazan R. Successful treatment of antibiotic-resistant poly-microbial bone infection with bacteriophages and antibiotics combination. Clin. Infect. Dis. 2019; 69(11):2015–8. DOI: 10.1093/cid/ciz222.

11. Perepanova T.S., Kazachenko A.V., Khazan P.L., Malova Yu.A. [Therapeutic applications of bacteriophages: back to the future]. Klinicheskaya Mikrobiologiya i Antimikrobnaya Khimioterapiya [Clinical Microbiology and Antimicrobial Chemotherapy]. 2021; 23(1):55–64. DOI: 10.36488/cmac.2021.1.55-64.

12. Totté J.E.E., van Doorn M.B., Pasmans S.G.M.A. Successful treatment of chronic Staphylococcus aureus-related dermatoses with the topical endolysin Staphefekt SA.100: a report of 3 cases. Case Rep. Dermatol. 2017; 9(2):19–25. DOI: 10.1159/000473872.

13. Nazarov P.A. [Alternatives to antibiotics: phage lytic enzymes and phage therapy]. Vestnik RGMU. [Bulletin of Russian State Medical University] 2018; (1):5–15. DOI: 10.24075/vrgmu.2018.002.

14. Sulakvelidze A., Alavidze Z., Morris J.G. Jr. Bacteriophage therapy. Antimicrob. Agents Chemother. 2001; 45(3):649–59. DOI: 10.1128/AAC.45.3.649-659.2001.

15. Gaevskaya N.E., Kochetkova A.O. [The new races of cholera bacteriophages perspective for applying in laboratory diagnostic of cholera]. Klinicheskaya Laboratornaya Diagnostika [Clinical Laboratory Diagnostics]. 2017; 62(7):440–3. DOI: 10.18821/0869-2084-2017-62-7-440-443.

16. Ovchinnikova M.V., Korovkina G.I., Gracheva I.V., Alenkina T.V. [Lysogenic system of non-epidemic cholera vibrio El Tor, resistant to diagnostic bacteriophage CTX-]. Problemy Osobo Opasnykh Infektsii [Problems of Particularly Dangerous Infections]. 2012; (2):43–5. DOI: 10.21055/0370-1069-2012-2(112)-43-45.

17. Vagima Y., Gur D., Aftalion M., Moses S., Levy Y., Makovitzki A., Holtzman T., Oren Z, Segula Y., Fatelevich E., Tidhar A., Zauberman A., Rotem S., Mamroud E., Steinberger-Levy I. Therapy potentiates second-line antibiotic treatment against pneumonic plague. Viruses. 2022; 14(4):688. DOI: 10.3390/v14040688.

18. Grigor’ev A.A., Borisevich I.V., Darmov I.V., Bondarev V.P., Kuznetsov S.L., Mironin A.V., Pogorelsky I.P., Letarov A.V., Koulikov E.E., Manykin A.A. [Isolation of GAL tularemia bacteriophage and its characteristics]. Problemy Osobo Opasnykh Infektsii [Problems of Particularly Dangerous Infections]. 2008; (98):33–6. DOI: 10.21055/0370-1069-2008-4(98)-33-36.

19. Taran I.F., Zanina V.M., Lyamkin G.I., Cybin B.P., Tikhenko N.I. [Comparative evaluation of the spectrum of lytic effects of bacteriophages TB, Wb, Fi, BK 2 and R on various Brucella species]. Zhurnal Mikrobiologii, Epidemiologii, Immunobiologii [Journal of Microbiology, Epidemiology, Immunobiology]. 1983; (2):48–52.

20. Aghebati-Maleki L., Bakhshinejad B., Baradaran B., Motallebnezhad M., Aghebati-Maleki A., Nickho H., Yousefi M., Majidi J. Phage display as a promising approach for vaccine development. J. Biomed. Sci. 2016; 23(1):66. DOI: 10.1186/s12929-016-0285-9.

21. Dunne M., Rupf B., Tala M., Qabrati X., Ernst P., Shen Y., Sumrall E., Heeb L., Plückthun A., Loessner M.J., Kilcher S. Reprogramming bacteriophage host range through structure-guided design of chimeric receptor binding proteins. Cell Reports. 2019; 29(5):1336–50.e4. DOI: 10.1016/j.celrep.2019.09.062.

22. Ofir G., Sorek R. Contemporary phage biology: from classic models to new insights. Cell. 2018; 172(6):1260–70. DOI: 10.1016/j.cell.2017.10.045.

23. Bertozzi Silva J., Storms Z., Sauvageau D. Host receptors for bacteriophage adsorption. FEMS Microbiol. Lett. 2016; 363(4):fnw002. DOI: 10.1093/femsle/fnw002.

24. Dou C., Xiong J., Gu Y., Yin K., Wang J., Hu Y., Zhou D., Fu X., Qi S., Zhu X., Yao S., Xu H., Nie C., Liang Z., Yang S., Wei Y., Cheng W. Structural and functional insights into the regulation of the lysis-lysogeny decision in viral communities. Nat. Microbiol. 2018; 3(11):1285–94. DOI: 10.1038/s41564-018-0259-7.

25. Howard-Varona C., Hargreaves K.R., Abedon S.T., Sullivan M.B. Lysogeny in nature: mechanisms, impact and ecology of temperate phages. ISME J. 2017; 11(7):1511–20. DOI: 10.1038/ismej.2017.16.

26. Bondy-Denomy J., Qian J., Westra E.R., Buckling A., Guttman D.S., Davidson A.R., Maxwell K.L. Prophages mediate defense against phage infection through diverse mechanisms. ISME J. 2016; 10(12):2854–66. DOI: 10.1038/ismej.2016.79.

27. Henrot C., Petit M.A. Signals triggering profage induction in the gut microbiota. Mol. Microbiol. 2022; 118(5):494–502. DOI: 10.1111/mmi.14983.

28. Shield C.G., Swift B.M.C., McHugh T.D., Dedrick R.M., Hatfull G.F., Satta G. Application of bacteriophages for mycobacterial infections, from diagnosis to treatment. Microorganisms. 2021; 9(11):2366. DOI: 10.3390/microorganisms9112366.

29. Modrich P. Structures and mechanisms of DNA restriction and modification enzymes. Q. Rev. Biophys. 1979; 12(3):315–69. DOI: 10.1017/s0033583500005461.

30. Katter E., Sulakvelidze A., editors. [Bacteriophages: Biology and Application]. Moscow: “Nauchny mir”; 2012. 636 p.

31. Salmond G.P., Fineran P.C. A century of the phage: past, present and future. Nat. Rev. Microbiol. 2015; 13(12):777–86. DOI: 10.1038/nrmicro3564.

32. Yang H., Zhang Y., Yu J., Huang Y., Zhang X.E., Wei H. Novel chimeric lysin with high-level antimicrobial activity against methicillin-resistant Staphylococcus aureus in vitro and in vivo. Antimicrob. Agents Chemother. 2014; 58(1):536–42. DOI: 10.1128/AAC.01793-13.

33. Djurkovic S., Loeffler J.M., Fischetti V.A. Synergistic killing of Streptococcus pneumoniae with the bacteriophage lytic enzyme Cpl-1 and penicillin or gentamicin depends on the level of penicillin resistance. Antimicrob. Agents Chemother. 2005; 49(3):1225–8. DOI: 10.1128/AAC.49.3.1225-1228.2005.

34. Ju Z., Sun W. Drug delivery vectors based on filamentous bacteriophages and phage-mimetic nanoparticles. Drug Delivery. 2017; 24(1):1898–908. DOI: 10.1080/10717544.2017.1410259.

35. Kostyukevich O.I. [The use of bacteriophages in clinical practice: the Renaissance]. Russky Meditsinsky Zhurnal [Russian Medical Journal]. 2015; (21):1258–62.

36. Aleksanina N.V., Tverdohlebova T.I. [Phage resistance of opportunistic bacteria of intestinal microbiota in children with microbiocenosis disorders]. Zhurnal Infektologii [Journal of Infectology]. 2021; 13(2):102–7. DOI: 10.22625/2072-6732-2021-13-2-102-107.

37. Bochkareva S.S., Karaulov A.V., Aleshkin A.V., Novikova L.I., Fedorova I.M., Blyakher M.S., Koteleva S.I., Kapustin I.V. [Methodological approaches to assessing some parameters of humoral and cellular immune response to bacteriophages.]. Klinicheskaya Laboratornaya Diagnostika [Clinical Laboratory Diagnostics]. 2019; 64(4):237–42. DOI: 10.18821/0869-2084-2019-64-4-237-242.

38. Dalmasso M., Hill C., Ross R.P. Exploting gut bacteriophages for human health. Trends Microbiol. 2014; 22(7):399–405. DOI: 10.1016/j.tim.2014.02.010.

39. De Sordi L., Lourenço M., Debarbieux L. “I will survive”: A tale of bacteriophage-bacteria coevolution in the gut. Gut Microbes. 2019; 10(1):92–9. DOI: 10.1080/19490976.2018.1474322.

40. Dufour N., Clermont O., La Combe B., Messika J., Dion S., Khanna V., Denamur E., Ricard J.D., Debarbieux L. Bacteriophage LM33_P1, a fast-acting weapon against the pandemic ST131-025b: H4 Escherichia coli clonal complex. J. Antimicrob. Chemother. 2016; 71(11):3072–80. DOI: 10.1093/jac/dkw253.

41. Kornienko E.A. [Gut microbiota as a key factor in the formation of immunity and tolerance. The possibilities of probiotics]. Medicinskiy Sovet [Medical Council]. 2020; (10):92–100. DOI: 10.21518/2079-701X-2020-10-92-100.

42. Van Belleghem J.D., Dąbrowska K., Vaneechoutte M., Barr J.J., Bollyky P.L. Interactions between bacteriophage, bacteria, and the mammalian immune system. Viruses. 2019; 11(1):10. DOI: 10.3390/v11010010.

43. Majewska J., Beta W., Lecion D., Hodyra-Stefaniak K., Kłopot A., Kaźmierczak Z.. Miernikiewicz P., Piotrowicz A., Ciekot J., Owczarek B., Kopciuch A., Wojtyna K., Harhala M., Mąkosa M., Dąbrowska K. Oral application of T4 phage induces weak antibody production in the gut and in the blood. Viruses. 2015; 7(8):4783–99. DOI: 10.3390/v7082845.

44. Duan Y., Young R., Schnabl B. Bacteriophages and their potential for treatment of gastrointestinal diseases. Nat. Rev. Gastroenterol. Hepatol. 2022; 19(2):135–44. DOI: 10.1038/s41575-021-00536-z.

45. Henry K.A., Murira A., van Houten N.E., Scot J.K. Developing strategies to enhance and focus humoral immune responses using filamentous phage as a model antigen. Bioeng. Bugs. 2011; 2(5):275–83. DOI: 10.4161/bbug.2.5.16559.

46. Zhang L., Hou X., Sun L., He T., Wei R., Pang M., Wang R. Staphylococcus aureus bacteriophage suppresses LPS-induced inflammation in MAC-T bovine mammary epithelial cells. Front. Microbiol. 2018; 9:1614. DOI: 10.3389/fmicb.2018.01614.

47. Gonchar N.V., Ermolenko K.D., Skripchenko N.V. [Personalized bacteriophage therapy of digestive diseases]. Zhurnal Infektologii [Journal of Infectology]. 2022; 14(2):47–54. DOI: 10.22625/2072-6732-2022-14-2-47-54.

48. Sweere J.M., Van Belleghem J.D., Ishak H., Bach M.S., Popescu M., Sunkari V., Kaber G., Manasherob R., Suh G.A., Cao X., de Vries C.R., Lam D.N., Marshall P.L., Birukova M., Katznelson E., Lazzareschi D.V., Balaji S., Keswani S.G., Hawn T.R., Secor P.R., Bollyky P.L. Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection. Science. 2019; 363(6434):eaat9691. DOI: 10.1126/science.aat9691.

49. Gogokhia L., Buhrke K., Bell R., Hoffman B., Brown D.G., Hanke-Gogokhia C., Ajami N.J., Wong M.C., Ghazaryan A., Valentine J.F., Porter N., Martens E., O’Connell R., Jacob V., Scherl E., Crawford C., Stephens W.Z., Casjens S.R., Longman R.S., Round J.L. Expansion of bacteriophages is linked to aggravated intestinal inflammation and colitis. Cell Host Microbe. 2019; 25(2):285–99.e8. DOI: 10.1016/j.chom.2019.01.008.

50. Grubb D.S., Wrigley S.D., Freedman K.E., Wei Y., Vazquez A.R., Trotter R.E., Wallace T.C., Johnson S.A., Weir T.L. PHAGE-2 study: supplemental bacteriophages extend Bifidobacterium animalis subsp. lactis BL04 benefits on gut health and microbiota in healthy adults. Nutrients. 2020; 12(8):2474. DOI: 10.3390/nu12082474.

51. Aslanov B.I., Lyubimova A.V., Zueva L.P. [Bacteriophages as effective anti-epidemic agents for stopping outbreaks of hospitalacquired infections]. Zhurnal Infektologii [Journal of Infectology]. 2019; 11(1):65–70. DOI: 10.22625/2072-6732-2019-11-1-65-70.

52. Babayan M.L. [The place of bacteriophages in the treatment of gastrointestinal diseases]. Mediysinskiy Sovet [Medical Council]. 2015; (14):64–72. DOI: 10.21518/2079-701X-2015-14-64-72.

53. Delyagin V.M. [Bacteriophage therapy at the present stage]. Russky Meditsinsky Zhurnal [Russian Medical Journal]. 2015; 23(3):132–6.

54. Merabishvili M., Pirnay J.P., De Vos D. Guidelines to compose an ideal bacteriophage cocktail. Methods Mol. Biol. 2018; 1693:99–110. DOI: 10.1007/978-1-4939-7395-8_9.

55. Vakarina A.A., Kataeva L.V., Stepanova T.F. [Influence of bacteriophages on sensitivity of conditionally pathogenic bacteria to antibacterial preparations]. Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii [Journal of Microbiology, Epidemiology and Immunobiology]. 2019; (2):3–7. DOI: 10.36233/0372-9311-2019-2-3-7.

56. Save J., Que Y.A., Entenza J.M., Kolenda C., Laurent F., Resch G. Bacteriophages combined with subtherapeutic doses of flucloxacillin act synergistically against Staphylococcus aureus experimental infectious endocarditis. J. Am. Heart Assoc. 2022; 11(3):e023080. DOI: 10.1161/JAHA.121.023080.

57. Lu H., Li Z., Elbaz A., Ni S.Q. Synergistic action of phages and lytic proteins with antibiotics: a combination strategy to target bacteria and biofilms. BMC Microbiol. 2023; 23(1):149. DOI: 10.1186/s12866-023-02881-2.

58. Zhao N., Li L., Luo G., Xie S., Lin Y., Han S., Huang Y., Zheng S. Multiplex gene editing and large DNA fragment deletion by the CRISPR/Cpf1RecE/T system in Corynebacterium glutamicum. J. Ind. Microbiol. Biotechnol. 2020; 47(8):599–608. DOI: 10.1007/s10295-020-02304-5.

59. Davidovich N.V., Kukalevskaya N.N., Bashilova E.N., Bazhukova T.A. [Basic principles of the evolution of antibiotic resistance in bacteria (literature review)]. Klinicheskaya Laboratornaya Diagnostika [Clinical Laboratory Diagnostics]. 2020; 65(6):387–93. DOI: 10.18821/0869-2084-2020-65-6-387-393.

60. Chen Y., Batra H., Dong J., Chen C., Rao V.B., Tao P. Genetic engineering of bacteriophages against infectious diseases. Front. Microbiol. 2019; 10:954. DOI: 10.3389/fmicb.2019.00954.