1932

Abstract

Antibiotic resistance in bacterial pathogens presents a substantial threat to the control of infectious diseases. Development of new classes of antibiotics has slowed in recent years due to pressures of cost and market profitability, and there is a strong need for new antimicrobial therapies. The therapeutic use of bacteriophages has long been considered, with numerous anecdotal reports of success. Interest in phage therapy has been renewed by recent clinical successes in case studies with personalized phage cocktails, and several clinical trials are in progress. We discuss recent progress in the therapeutic use of phages and contemplate the key factors influencing the opportunities and challenges. With strong safety profiles, the main challenges of phage therapeutics involve strain variation among clinical isolates of many pathogens, battling phage resistance, and the potential limitations of host immune responses. However, the opportunities are considerable, with the potential to enhance current antibiotic efficacy, protect newly developed antibiotics, and provide a last resort in response to complete antibiotic failure.

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/content/journals/10.1146/annurev-med-080219-122208
2022-01-27
2024-06-17
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Literature Cited

  1. 1. 
    Summers WC. 1999. Felix d'Herelle and the Origins of Molecular Biology New Haven, CT: Yale Univ. Press
    [Google Scholar]
  2. 2. 
    Aiello AE, Larson EL, Sedlak R. 2008. The health revolution: medical and socioeconomic advances. Am. J. Infect. Control. 36:S116–27
    [Google Scholar]
  3. 3. 
    Chanishvili N. 2012. Phage therapy—history from Twort and d'Herelle through Soviet experience to current approaches. Adv. Virus Res. 83:3–40
    [Google Scholar]
  4. 4. 
    Kortright KE, Chan BK, Koff JL, Turner PE. 2019. Phage therapy: a renewed approach to combat antibiotic-resistant bacteria. Cell Host Microbe 25:219–32
    [Google Scholar]
  5. 5. 
    Luong T, Salabarria AC, Roach DR. 2020. Phage therapy in the resistance era: Where do we stand and where are we going?. Clin. Ther. 42:1659–80
    [Google Scholar]
  6. 6. 
    Shrivastava SR, Shrivastava PS, Ramasamy J. 2018. Responding to the challenge of antibiotic resistance: World Health Organization. J. Res. Med. Sci. 23:21
    [Google Scholar]
  7. 7. 
    Lewis K. 2020. The science of antibiotic discovery. Cell 181:29–45
    [Google Scholar]
  8. 8. 
    Wommack KE, Colwell RR. 2000. Virioplankton: viruses in aquatic ecosystems. Microbiol. Mol. Biol. Rev. 64:69–114
    [Google Scholar]
  9. 9. 
    Mushegian AR. 2020. Are there 1031 virus particles on Earth, or more, or fewer?. J. Bacteriol. 202:e00052-20
    [Google Scholar]
  10. 10. 
    Hendrix RW, Smith MC, Burns RN et al. 1999. Evolutionary relationships among diverse bacteriophages and prophages: all the world's a phage. PNAS 96:2192–97
    [Google Scholar]
  11. 11. 
    Hendrix RW. 2002. Bacteriophages: evolution of the majority. Theor. Popul. Biol. 61:471–80
    [Google Scholar]
  12. 12. 
    Hatfull GF. 2020. Actinobacteriophages: genomics, dynamics, and applications. Annu. Rev. Virol. 7:37–61
    [Google Scholar]
  13. 13. 
    Knowles B, Silveira CB, Bailey BA et al. 2016. Lytic to temperate switching of viral communities. Nature 531:466–70
    [Google Scholar]
  14. 14. 
    Davies EV, Winstanley C, Fothergill JL, James CE. 2016. The role of temperate bacteriophages in bacterial infection. FEMS Microbiol. Lett. 363:fnw015
    [Google Scholar]
  15. 15. 
    Luque A, Silveira CB. 2020. Quantification of lysogeny caused by phage coinfections in microbial communities from biophysical principles. mSystems 5:e00353-20
    [Google Scholar]
  16. 16. 
    Luong T, Salabarria AC, Roach DR. 2020. Phage therapy in the resistance era: Where do we stand and where are we going?. Clin. Ther. 42:1659–80
    [Google Scholar]
  17. 17. 
    Schooley RT, Biswas B, Gill JJ et al. 2017. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob. Agents Chemother 61:e00954-17Describes the first therapeutic use of bacteriophages to treat an A. baumannii infection.
    [Google Scholar]
  18. 18. 
    Dedrick R, Guerrero Bustamante C, Garlena RA et al. 2019. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat. Med. 25:730–33The first therapeutic use of bacteriophages to treat a Mycobacterium infection, and the first use of engineered bacteriophages in a patient.
    [Google Scholar]
  19. 19. 
    Jault P, Leclerc T, Jennes S et al. 2018. Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial. Lancet Infect. Dis 19:35–45Clinical trial to treat P. aeruginosa–infected burn wounds with phages.
    [Google Scholar]
  20. 20. 
    Sarker SA, Sultana S, Reuteler G et al. 2016. Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: a randomized trial in children from Bangladesh. EBioMedicine 4:124–37The first clinical trial of phage therapy to treat E. coli infections in children.
    [Google Scholar]
  21. 21. 
    Chan BK, Turner PE, Kim S et al. 2018. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol. Med. Public Health 2018.60–66
    [Google Scholar]
  22. 22. 
    Chan BK, Sistrom M, Wertz JE et al. 2016. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Sci. Rep. 6:26717
    [Google Scholar]
  23. 23. 
    Marinelli LJ, Piuri M, Swigonova Z et al. 2008. BRED: a simple and powerful tool for constructing mutant and recombinant bacteriophage genomes. PLOS ONE 3:e3957
    [Google Scholar]
  24. 24. 
    Khalid A, Lin RCY, Iredell JR. 2020. A phage therapy guide for clinicians and basic scientists: background and highlighting applications for developing countries. Front. Microbiol 11:599906
    [Google Scholar]
  25. 25. 
    Petrovic Fabijan A, Lin RCY, Ho J et al. 2020. Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat. Microbiol. 5:465–72
    [Google Scholar]
  26. 26. 
    Schooley RT, Strathdee S. 2020. Treat phage like living antibiotics. Nat. Microbiol. 5:391–92
    [Google Scholar]
  27. 27. 
    Aslam S, Lampley E, Wooten D et al. 2020. Lessons learned from the first 10 consecutive cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections at a single center in the United States. Open Forum Infect. Dis 7:ofaa389Lessons from the first 10 cases of phage therapy at iPATH, the first phage therapy center in the United States.
    [Google Scholar]
  28. 28. 
    Chan BK, Stanley G, Modak M et al. 2021. Bacteriophage therapy for infections in CF. Pediatr. Pulmonol. 56:Suppl. 1S4–9
    [Google Scholar]
  29. 29. 
    Carrigy NB, Chang RY, Leung SSY et al. 2017. Anti-tuberculosis bacteriophage D29 delivery with a vibrating mesh nebulizer, jet nebulizer, and soft mist inhaler. Pharm. Res 34:2084–96
    [Google Scholar]
  30. 30. 
    Van Belleghem JD, Manasherob R, Miedzybrodzki R et al. 2020. The rationale for using bacteriophage to treat and prevent periprosthetic joint infections. Front. Microbiol. 11:591021
    [Google Scholar]
  31. 31. 
    Hatfull GF. 2014. Mycobacteriophages: windows into tuberculosis. PLOS Pathogens 10:e1003953
    [Google Scholar]
  32. 32. 
    Moller AG, Winston K, Ji S et al. 2021. Genes influencing phage host range in Staphylococcus aureus on a species-wide scale. mSphere 6:e01263-20
    [Google Scholar]
  33. 33. 
    Guerrero Bustamante C, Dedrick RM, Garlena RA et al. 2021. Towards a phage cocktail for tuberculosis: susceptibility and tuberculocidal action of mycobacteriophages against diverse Mycobacterium tuberculosis strains. mBio 12:e00973-21
    [Google Scholar]
  34. 34. 
    Dedrick RM, Freeman KG, Nguyen JA et al. 2021. Potent antibody-mediated neutralization limits bacteriophage treatment of a pulmonary Mycobacterium abscessus infection. Nat. Med. 27:135761
    [Google Scholar]
  35. 35. 
    Jerne NK, Avegno P. 1956. The development of the phage-inactivating properties of serum during the course of specific immunization of an animal: reversible and irreversible inactivation. J. Immunol. 76:200–8
    [Google Scholar]
  36. 36. 
    Roach DR, Leung CY, Henry M et al. 2017. Synergy between the host immune system and bacteriophage is essential for successful phage therapy against an acute respiratory pathogen. Cell Host Microbe 22:38–47.e4
    [Google Scholar]
  37. 37. 
    Hodyra-Stefaniak K, Miernikiewicz P, Drapala J et al. 2015. Mammalian host-versus-phage immune response determines phage fate in vivo. Sci. Rep. 5:14802
    [Google Scholar]
  38. 38. 
    Gorski A, Miedzybrodzki R, Borysowski J et al. 2012. Phage as a modulator of immune responses: practical implications for phage therapy. Adv. Virus Res. 83:41–71
    [Google Scholar]
  39. 39. 
    Wetzel KS, Guerrero-Bustamante CA, Dedrick RM et al. 2021. CRISPY-BRED and CRISPY-BRIP: efficient bacteriophage engineering. Sci. Rep 11:6796
    [Google Scholar]
  40. 40. 
    Ford ME, Sarkis GJ, Belanger AE et al. 1998. Genome structure of mycobacteriophage D29: implications for phage evolution. J. Mol. Biol. 279:143–64
    [Google Scholar]
  41. 41. 
    Russell DA. 2018. Sequencing, assembling, and finishing complete bacteriophage genomes. Methods Mol. Biol. 1681:109–25
    [Google Scholar]
  42. 42. 
    Pires DP, Cleto S, Sillankorva S et al. 2016. Genetically engineered phages: a review of advances over the last decade. Microbiol. Mol. Biol. Rev. 80:523–43
    [Google Scholar]
  43. 43. 
    Sarkis GJ, Jacobs WR Jr., Hatfull GF. 1995. L5 Luciferase reporter mycobacteriophages: a sensitive tool for the detection and assay of live mycobacteria. Mol. Microbiol. 15:1055–67
    [Google Scholar]
  44. 44. 
    Jacobs WR Jr., Tuckman M, Bloom BR 1987. Introduction of foreign DNA into mycobacteria using a shuttle phasmid. Nature 327:532–35
    [Google Scholar]
  45. 45. 
    Chauthaiwale VM, Therwath A, Deshpande VV 1992. Bacteriophage lambda as a cloning vector. Microbiol. Rev. 56:577–91
    [Google Scholar]
  46. 46. 
    Hatoum-Aslan A. 2018. Phage genetic engineering using CRISPR–Cas systems. Viruses 10:335
    [Google Scholar]
  47. 47. 
    Marinelli LJ, Piuri M, Hatfull GF. 2019. Genetic manipulation of lytic bacteriophages with BRED: bacteriophage recombineering of electroporated DNA. Methods Mol. Biol. 1898:69–80
    [Google Scholar]
  48. 48. 
    Pan YJ, Lin TL, Chen CC et al. 2017. Klebsiella phage ΦK64–1 encodes multiple depolymerases for multiple host capsular types. J. Virol. 91:e02457-16
    [Google Scholar]
  49. 49. 
    Feher T, Karcagi I, Blattner FR, Posfai G. 2012. Bacteriophage recombineering in the lytic state using the lambda red recombinases. Microb. Biotechnol. 5:466–76
    [Google Scholar]
  50. 50. 
    Shin H, Lee JH, Yoon H et al. 2014. Genomic investigation of lysogen formation and host lysis systems of the Salmonella temperate bacteriophage SPN9CC. Appl. Environ. Microbiol. 80:374–84
    [Google Scholar]
  51. 51. 
    Payaslian F, Gradaschi V, Piuri M 2020. Genetic manipulation of phages for therapy using BRED. Curr. Opin. Biotechnol. 68:8–14
    [Google Scholar]
  52. 52. 
    Jones WD Jr., David HL. 1971. Inhibition by fifampin of mycobacteriophage D29 replication in its drug-resistant host, Mycobacterium smergmatis ATCC 607. Am. Rev. Respir. Dis. 103:618–24
    [Google Scholar]
  53. 53. 
    Gu Liu C, Green SI, Min L et al. 2020. Phage-antibiotic synergy is driven by a unique combination of antibacterial mechanism of action and stoichiometry. mBio 11:e01462-20
    [Google Scholar]
  54. 54. 
    Rohde C, Resch G, Pirnay JP et al. 2018. Expert opinion on three phage therapy related topics: bacterial phage resistance, phage training and prophages in bacterial production strains. Viruses 10:178
    [Google Scholar]
  55. 55. 
    Dedrick RM, Smith BE, Garlena RA et al. 2021. Mycobacterium abscessus strain morphotype determines phage susceptibility, the repertoire of therapeutically useful phages, and phage resistance. mBio 12:e03431-20
    [Google Scholar]
  56. 56. 
    Bernheim A, Sorek R. 2020. The pan-immune system of bacteria: antiviral defence as a community resource. Nat. Rev. Microbiol. 18:113–19
    [Google Scholar]
  57. 57. 
    Khawaldeh A, Morales S, Dillon B et al. 2011. Bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection. J. Med. Microbiol. 60:1697–700
    [Google Scholar]
  58. 58. 
    Gordillo Altamirano F, Forsyth JH, Patwa R et al. 2021. Bacteriophage-resistant Acinetobacter baumannii are resensitized to antimicrobials. Nat. Microbiol. 6:157–61
    [Google Scholar]
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