Timeline | Published:

The prospect for bacteriophage therapy in Western medicine

Nature Reviews Drug Discovery volume 2, pages 489497 (2003) | Download Citation

Subjects

Abstract

Bacteriophage (phage) have been used for clinical applications since their initial discovery at the beginning of the twentieth century. However, they have never been subjected to the scrutiny — in terms of the determination of efficacy and pharmacokinetics of therapeutic agents — that is required in countries that enforce certification for marketed pharmaceuticals. There are a number of historical reasons for this deficiency, including the overshadowing discovery of the antibiotics. Nevertheless, present efforts to develop phage into reliable antibacterial agents have been substantially enhanced by knowledge gained concerning the genetics and physiology of phage in molecular detail during the past 50 years. Such efforts will be of importance given the emergence of antibiotic-resistant bacteria.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States: results from the TRUST Surveillance Program, 1999–2000. Clin. Infect. Dis. 34, S4–S16 (2002).

  2. 2.

    National Center for Infectious Diseases. Campaign to prevent antimicrobial resistance in healthcare settings. Centers for Disease Control and Prevention [online] (cited 30 Sep 2002) <> (2002).

  3. 3.

    Drug resistance of methicillin-resistant Staphylococcus aureus (MRSA) in Japan until 1993. Jpn J. Antibiot. 47, 575–584 (1994).

  4. 4.

    An investigation on the nature of ultra-microscopic viruses. Lancet 2, 1241–1243 (1915). This paper presents the original discovery of bacterial viruses.

  5. 5.

    The Bacteriophage and its Behavior 490–541 (Williams & Wilkins, Baltimore, Maryland, 1926). Although much of the material in this book is dated, it still contains observations of interest.

  6. 6.

    Felix d'Herelle and the origins of Molecular Biology 125–144 (Yale University Press, New Haven and London, 2001).

  7. 7.

    Bacteriophage therapy. Annu. Rev. Microbiol. 55, 437–451 (2001).

  8. 8.

    , , , & Bacteriophages show promise as antimicrobial agents. J. Infect. 16, 5–15 (1998). This and the following article present an overall review of phage therapy efforts in Poland and the Soviet Union.

  9. 9.

    , & Bacteriophage therapy. Antimicrob. Agents Chemother. 45, 649–659 (2001).

  10. 10.

    & Studies on commercial bacteriophage products. JAMA 100, 110–113 (1933). Insights into the problems associated with pharmaceutical phage preparations.

  11. 11.

    Bacteriophage in clinical medicine. J. Lab. Clin. Med. 17, 675–680 (1932).

  12. 12.

    Bacteriological and physiological research styles in the early controversy on the nature of the bacteriophage phenomenon. Med. Hist. 36, 243–270 (1992).

  13. 13.

    & Isolation of the bacteriophage λ receptor from Escherichia coli. J. Bacteriol. 116, 1436–1446 (1973).

  14. 14.

    & Bacteriophage therapy. JAMA 103, 1769–1776, 1847–1853 & 1934–1939 (1934).

  15. 15.

    Bacteriophage therapy for bacterial infections. Perspect. Biol. Med. 44, 1–16 (2001).

  16. 16.

    & Bacteriophage therapy and prophylaxis: rediscovery and renewed assessment of potential. Trends Microbiol. 5, 268–271 (1997)

  17. 17.

    Inactivation of antistreptococcus bacteriophage by animal fluids. Public Health Rep. 48, 411–426 (1933).

  18. 18.

    , & The multiplication of bacteriophage in vivo and its protective effects against experimental infection with Shigella dysenteria. J. Exp. Med. 20, 161–168 (1943). This paper presents crucial experiments designed to explore the mechanisms underlying the therapeutic effects observed when using phage to treat a systemic bacterial infection.

  19. 19.

    , & The effect of an anti-vi bacteriophage on typhoid infection in mice. Lancet 319–320 (1937).

  20. 20.

    Molecular Biology of Bacterial Viruses (W. H. Freeman, San Francisco, 1963). Essential information for those interested in phage and their applications, and provides insights into theories concerning phage therapy failures.

  21. 21.

    et al. Bacteriophage therapy rescues mice bacteremic from a clinical isolate of vancomycin-resistant Enterococcus faecium. Infect. Immun. 70, 204–210 (2002). In addition to a demonstration of the effectiveness of phage therapy for treatment of animals infected with antibiotic resistant bacteria, the experiments in this study also show that the rescue of infected animals is directly dependent on phage function.

  22. 22.

    et al. Experimental protection of mice against lethal Staphylococcus aureus infection by novel bacteriophage MR11. J. Infect. Dis. 187, 613–624 (2003). The animal experiments described in this paper provide evidence that phage could provide an alternate therapeutic approach for the treatment of a serious antibiotic-resistant bacterial infection.

  23. 23.

    Treatment of experimental infections of mice with bacteriophages. J. Med. Microbiol. 37, 258–262 (1992).

  24. 24.

    , , & Phage therapy of local and systemic disease caused by Vibrio vulnificus in iron-dextran-treated mice. Infect. Immun. 70, 6251–6262 (2002).

  25. 25.

    et al. Killing of Mycobacterium avium and Mycobacterium tuberculosis by a mycobacteriophage delivered by a nonvirulent mycobacterium: a model for phage therapy of intracellular bacterial pathogens. J. Infect. Dis. 186, 1155–1160 (2002). Intracellular bacterial infections are often difficult to treat and this paper provides evidence that phage could provide a therapeutic approach to this problem.

  26. 26.

    & Successful treatment of experimental E. coli infections in mice using phage: its general superiority over antibiotics. J. Gen. Microbiol. 128, 307–318 (1982). This is a crucial study in which fewer resistant bacterial colonies were found following phage therapy than found following antibiotic therapies, and the phage-resistant bacterial colonies were reported to have alterations in their capsules associated with reduced pathogenic properties.

  27. 27.

    , & The control of experimental E. coli diarrhea in calves by means of bacteriophages. J. Gen. Microbiol. 133, 1111–1126 (1987).

  28. 28.

    , & Factors influencing the survival and multiplication of bacteriophages in calves and their environments. J. Gen. Microbiol. 133, 1127–1135 (1987).

  29. 29.

    , & Prevention of Clostridium difficile-induced ileocecitis with bacteriophage. Anaerobe 5, 69–78 (1999).

  30. 30.

    Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa. Burns 20, 209–211 (1994).

  31. 31.

    & Bacteriophage therapy for infectious diseases in aquiculture. Res. Microbiol. 153, 13–18 (2002).

  32. 32.

    , , , & H-mutant bacteriophages as a potential biocontrol of bacterial blight of geraniums. Hortscience 36, 90–100 (2001).

  33. 33.

    , , , & Control of bacterial spot on tomato in the greenhouse and field with H-mutant bacteriophages. Hortscience 35, 882–884 (2000).

  34. 34.

    , & The fate of bacteriophage λ in non-immune germ-free mice. Nature 246, 221–223 (1973). This paper highlights the distribution of functional phage administered by various routes in mice and it presents evidence that oral administration is an ineffective method for achieving a systemic distribution of phage.

  35. 35.

    Le bacteriophage dans l'organisme. Comp. Rend. Soc. de Biol. (Paris) 85, 722–724 (1921).

  36. 36.

    & Accumulation of bacteriophage in spleen and liver following its intravenous inoculation. Proc. Soc. Exper. Biol. Med. 31, 901–905 (1934).

  37. 37.

    The activity of mouse kupffer cells following intravenous injection of T4 bacteriophage. Clin. Exp. Immunol. 5, 173–187 (1969). The crucial role of the liver in removing phage from the circulation of mammals is clearly delineated in this study.

  38. 38.

    et al. Long-circulating bacteriophage as antibacterial agents. Proc. Natl Acad. Sci. USA 93, 3188–3192 (1996). This paper describes the development of a selection technique, based on the recognition that the efficacy of phage therapy might be impaired by the mammalian innate immune system, for obtaining long-circulating phage with enhanced therapeutic properties.

  39. 39.

    et al. On the insertion of foreign DNA into mammalian genomes: mechanism and consequences. Gene 157, 241–245 (1995).

  40. 40.

    , , & On the fate of orally ingested foreign DNA in mice: chromosomal association and placental transmission to the fetus. Mol. Gen. Genet. 259, 569–576 (1998).

  41. 41.

    , , & Foreign (M13) DNA ingested by mice reaches peripheral leukocytes, spleen, and liver via the intestinal wall mucosa and can be covalently linked to mouse DNA. Proc. Natl Acad. Sci. USA 94, 961–966 (1997).

  42. 42.

    , & Bacterial virus gene expression in human cells. Nature 233, 398–400 (1971).

  43. 43.

    , , & Gene transfer to human cells: transducing phage λ plac gene expression in GM1-gangliosidosis fibroblasts. Proc. Natl Acad. Sci. USA 72, 3531–3535 (1975).

  44. 44.

    et al. Evolving phage vectors for cell targeted gene delivery. Curr. Pharm. Biotechnol. 3, 45–57 (2002).

  45. 45.

    & Immunogenic effect of bacteriophage in patients subjected to phage therapy. Arch Immunol. Ther. Exp. (Warsz.) 35, 553–561 (1987).

  46. 46.

    & Phage therapy revisited: the population biology of a bacterial infection and its treatment with bacteriophage and antibiotics. Am. Nat. 147, 881–898 (1996).

  47. 47.

    & A. Pharmacokinetic principles of bacteriophage therapy. Clin. Pharmacokinet. 42, 315–325 (2003).

  48. 48.

    et al. Visualizing Pneumococcal infections in the lungs of live mice using bioluminescent Streptococcus pneumoniae transformed with a novel Gram-positive lux transposon. Infect. Immun. 69, 3350–3358 (2001). Visualization methods presented in this study could facilitate the study of bacterial infections and their treatment.

  49. 49.

    , & Immunologic responses to bacteriophage φX174 in immunodeficiency diseases. J. Clin. Invest. 50, 2559–2568 (1971). This paper presents some of the initial experiments using phage to probe the human and mammalian immune systems.

  50. 50.

    , , , & Regulation of antibody responses: the role of complement and adhesion molecules. Clin. Immunol. Immunopathol. 3, S33–S40 (1993).

  51. 51.

    , , , & The antibody response to bacteriophage is linked to the lymphopenia gene in congenic BioBreeding rats. FEMS Immunol. Med. Microbiol. 32, 205–209 (2002).

  52. 52.

    , & Antibody studies in hypogammaglobulinemia. J. Clin. Invest. 45, 1593–1600 (1966).

  53. 53.

    , , & High-resolution mapping of the B cell epitopes of staphylokinase in humans using negative selection of a phage-displayed antigen library. J. Immunol. 161, 3161–3168 (1998).

  54. 54.

    Antibiotic-associated diarrhea. N. Engl. J. Med. 346, 334–339 (2002).

  55. 55.

    , , & Bacteriophage K1-5 encodes two different tail fiber proteins allowing it to infect and replicate on both K1 and K5 strains of E. coli. J. Virol. 75, 2509–2515 (2001). Adaptations of the phage construct presented in this paper could provide a general approach for the extension of the bacterial host range of phage.

  56. 56.

    , & Bacteriophage SP6 is closely related to phages K1-5, K5 and K1E but encodes a tail protein very similar to that of the distantly related P22. J. Bacteriol. 184, 2833–2836 (2002).

  57. 57.

    Acquisition and rearrangement of sequence motifs in the evolution of bacteriophage tail fibres. Mol. Microbiol. 12, 343–350 (1994).

  58. 58.

    et al. Reverse transcriptase-mediated tropism switching in bordetella bacteriophage. Science 295, 2091–2094 (2002).

  59. 59.

    & Entry of bacteriophage T7 DNA into the cell and escape from host restriction. J. Bacteriol. 170, 2095–2105 (1988).

  60. 60.

    Impossible vaccine tames Staphylococcus aureus. The Scientist 16, 24–28 (2002).

  61. 61.

    et al. The cell surface protein Ag43 facilitates phage infection of Escherichia coli in the presence of bile salts and carbohydrates. Microbiology 148, 1533–1542 (2002).

  62. 62.

    , , & The outer membrane protein, antigen 43, mediates cell-to-cell interactions within Escherichia coli biofilms. Mol. Microbiol. 37, 424–432 (2000).

  63. 63.

    Behavior of bacteriophage in body fluids and in exudates. J. Infect. Dis. 51, 527–541 (1932).

  64. 64.

    Action de la bile sur bacteriophage et importance de cette action. Compt. Rend. Soc. De biol. (Paris) 92, 1442–1443 (1925).

  65. 65.

    & Bacteriophage control of bacterial virulence. Infect. Immun. 70, 3985–3993 (2002).

  66. 66.

    , , , & Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

  67. 67.

    , , & Construction of luciferase reporter bacteriophage A511::luxAB for rapid and sensitive detection of viable Listeria cells. Appl. Environ. Microbiol. 62, 1133–1140 (1996).

  68. 68.

    et al. Conditionally replicating luciferase reporter phages: improved sensitivity for rapid detection and assessment of drug susceptibility of Mycobacterium tuberculosis. J. Clin. Microbiol. 35, 3232–3239 (1997).

  69. 69.

    , & A bacteriolytic agent that detects and kills Bacillus anthracis. Nature 418, 884–889 (2002).

  70. 70.

    MALDI-TOF mass spectrometry of bacteria. Mass Spectrom. Rev. 20, 172–194 (2001).

  71. 71.

    Characterization of bacteria by matrix-assisted laser desorption/ionisation and electrospray mass spectrometry. FEMS Microbiol. Rev. 24, 193–219 (2000).

  72. 72.

    et al. Consensus PCR and microarray for diagnosis of the genus Staphylococcus species and methicillin resistance. BioTechniques 31, 1364–1366, 1368, 1370–1372 (2001).

  73. 73.

    , & Antibody formation: III. the primary and secondary antibody response to bacteriophage ψX 174 in guinea pigs. J. Exp. Med. 115, 655–670 (1962).

  74. 74.

    Smaller fleas...ad infinitum: therapeutic bacteriophage redux. Proc. Natl Acad. Sci. USA 93, 3167–3168 (1996). This review stresses the need for additional research to facilitate the use of these viruses as safe and effective therapeutic antibacterial agents.

  75. 75.

    Superbugs reveal chink in armour. Nature 417, 477 (2002).

  76. 76.

    FDA restricts antibiotic use in livestock to protect people. The Wall Street Journal D3 (12 September, 2002).

  77. 77.

    et al. Isolation of bacteriophages from commercial sera. In Vitro 8, 91–93 (1972).

  78. 78.

    Phage in human vaccines. Science 188, 8 (1975).

  79. 79.

    , , & A protein antibiotic in the phage Qb virion: diversity in lysis targets. Science 292, 2326–2329 (2001).

  80. 80.

    , & Prevention and elimination of upper respiratory colonization of mice by group A streptococci by using a bacteriophage lytic enzyme. Proc. Natl Acad. Sci. USA 98, 4107–4112 (2001).

  81. 81.

    , , & Gene cloning and expression and secretion of Listeria monocytogenes bacteriophage-lytic enzymes in Lactococcus lactis. Appl. Environ. Microbiol. 66, 2951–2958 (2000).

  82. 82.

    & Bacteriophage in the treatment of plague. Ind. J. Med. Res. 19, 737–748 (1932).

  83. 83.

    , & Bacteriophage–bacteriophage interactions in the evolution of pathogenic bacteria. Trends Microbiol. 9, 137–144 (2001).

Download references

Author information

Affiliations

  1. Section on Biochemical Genetics, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.  merrilc@helix.nih.gov  dscholl@helix.nih.gov

    • Carl R. Merril
    •  & Dean Scholl
  2. Section of Developmental Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.  sadhya@helix.nih.gov

    • Sankar L. Adhya

Authors

  1. Search for Carl R. Merril in:

  2. Search for Dean Scholl in:

  3. Search for Sankar L. Adhya in:

Glossary

ADAPTIVE IMMUNE SYSTEM

The arm of the immune system that mounts an antigen-specific immune response as the result of the clonal selection of antigen-specific lymphocytes. Such lymphocytes produce antibodies that react with the antigen. The adaptive immune responses differ from the innate and non-adaptive immune system, which does not depend on clonal selection of antigen-specific lymphocytes.

BIOFILM

A structure made up of a community of bacteria composed of microcolonies and water channels that survives at a liquid interface. Such biofilms play a role in the pathogenic effects of bacterial infections associated with gingivitis, colitis, vaginitis, urethritis, conjunctivitis and otitis.

ENDOTOXINS

Components of bacterial cells that are usually associated with the lipopolysaccharide components of the outer layer of Gram-negative bacterial cell walls that are toxic (to mammals). Endotoxins are released in large quantities upon lysis of Gram-negative bacterial cells.

ENDOSIALIDASES

Enzymes that cleave at the sialic acid residue sites of the complex oligosaccharides associated with the protective capsule of many bacterial strains.

EXOTOXINS

A broad class of factors released by pathogenic bacteria that can harm infected mammals. Examples of such exotoxins are botulism toxin (Clostridium botulinum), streptolysins (Streptococcus pyogenes) and diphtheria toxin (Corynebacterium diptheriae).

IATROGENIC

An effect that is induced in a patient by a physician's activity or therapy; such effects often occur as complications of treatments for infectious diseases.

LD50

The amount of a substance that causes the death of 50% of test subjects.

LYSATE

The colloidal bacterial growth media remaining after phage replicate and kill the host cells. Lysates contain phage progeny, bacterial cell wall debris and, often, internal cellular components (for example, proteins, nucleic acids, small molecules and so on).

LYSOGENIC PHAGE

Phage that are capable of integrating their genome (that is, lysogenize) into the host chromosome. Such phages often mediate horizontal gene transfer (transduction) between bacterial strains. Most lysogenic phage can also go through a lytic cycle to produce more phage, often after induction (from some environmental factor).

LYTIC PHAGE

Phage that infect bacterial cells to replicate and then lyse the bacterial host.

NEO-ANTIGEN

An antigen for which animals or humans being studied have no pre-existing antibodies. The phage φX174, which is highly immunogenic, has served as such a neo-antigen in studies of human antibody responses, as most humans have no pre-existing antibodies to this phage.

PHAGE

Bacterial viruses. The term phage is used as both singular and plural when referring to phage(s) that is/are member(s) of a single phage strain. However, when referring to phage in more than one strain the plural is phages.

PHAGE PLAQUE

The lesion formed when a phage particle is applied to a film of a susceptible bacterial strain that is growing on an agar surface. The lesion results from the infection of a bacterial cell by a phage particle, followed by the production of phage progeny and their release by lysis, followed by the infection and lysis of additional bacterial cells in the vicinity of the initial infection.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrd1111