Phage therapy

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A phage injects its genome into a bacterial cell
Electron microscope image of bacteriophage attached to a bacterial cell. These viruses are the size and shape of the coliphage T1

Phage therapy is the therapeutic use of bacteriophages to treat disease-causing bacterial infections . Phages are viruses that specialize in bacteria and primordial bacteria as host cells . Phage therapy has been developed and used mainly in countries of the former Soviet Union , particularly Georgia , since the 1920s to treat a range of bacterial and polymicrobial biofilm infections. Phage therapy has many potential uses in human medicine, dentistry, veterinary medicine, agriculture, and food safety. If the host organism to which the process is applied is not an animal, we speak of biological pest control .

Bacteriophages are far more specific than the antibiotics normally used . In principle, they can be selected in such a way that they are not only harmless to the host organism (humans, animals or plants), but also to beneficial bacteria such as the intestinal flora , which reduces the risk of opportunistic infections . However, this specificity of phages has a disadvantage: a phage will only kill a bacterium if it belongs to a specific bacterial strain. Therefore, phage mixtures are often used to increase the success of the treatment. Alternatively, a suitable phage can be identified and grown using a sample of the bacteria to be controlled.

Phages are used therapeutically , especially in Georgia , to treat bacterial infections that do not respond to conventional antibiotics. Phages tend to be more successful than antibiotics where a bacterial biofilm is covered by a layer of polysaccharides that antibiotics typically cannot penetrate. In the West, no phage therapies are currently approved for use on humans.

In 2019, Rebekah M. Dedrick and colleagues reported on the successful treatment of a 15-year-old female patient with phages ("Muddy", "ZoeJ" and "BPs", Siphoviridae ), some of which were genetically engineered , for whom other therapies had previously failed; it was reported several times in the German media.

In addition, phages are used to combat Listeria and Salmonella in foods to prevent food poisoning .

history

Frederick Twort
Phage in action in Bacillus anthracis

After the discovery of bacteriophages by Frederick Twort and Felix d'Hérelle in 1915 and 1917, phage therapy was immediately recognized by many scientists as a decisive advance in the fight against infectious diseases. Georgi Eliava , a Georgian, made similar discoveries. He traveled to the Pasteur Institute in Paris and met d'Hérelle there. In 1923 he founded the Eliava Institute for Phage Research in Tbilisi .

In neighboring countries, u. a. in Russia, soon began extensive research and development activities. In the USA, the pharmaceutical company Eli Lilly and Company began offering phage therapy as a commercial product in the 1940s .

While knowledge of the biology of phages and the correct use of cocktails was thus gained, the early uses of phage therapy were often unreliable. When antibiotics were discovered in 1941 and widely marketed in the United States and Europe, most western scientists lost interest in further developing phage therapy.

Cut off from the western advances in antibiotic production of the 1940s, Russian scientists further developed the already successful phage therapy to treat the wounds of soldiers in field hospitals . During the Second World War , many soldiers in the Soviet Union were treated with phages that were suspected of various bacterial diseases such as: B. Dysentery or gangrene suffered. The success rate was just as good, if not better, compared to that of any antibiotic. Russian researchers developed and refined their treatment methods and published about them. However, because of the barriers the Cold War placed on science, this knowledge was not translated and could not be disseminated worldwide. A summary of these publications was published in 2011 in English: A Literature Review of the Practical Application of Bacteriophage Research .

The Eliava Institute in Tbilisi has an extensive library and research center. Phage therapy is now a widespread form of treatment in this region. Georgian doctors have been treating local patients, including infants and newborns, with phage since 1930.

With the development of antibiotic resistance since the 1950s and an advanced level of knowledge, there has been renewed interest worldwide in the possibility of using phage therapy along with other strategies to eradicate bacterial infections and chronic polymicrobial biofilms.

Phages have been studied as a possible means to kill pathogens like Campylobacter in raw food and Listeria in fresh food, or to fight bacteria that cause food to spoil. In agricultural practice, phages have been used to control pathogens such as Campylobacter , Escherichia and Salmonella in farm animals, Lactococcus and Vibrions in fish in aquaculture and Erwinia and Xanthomonas in farm plants. The oldest area of ​​application, however, was human medicine. Phages have been used against diarrheal diseases caused by Escherichia coli , Shigella and Vibrio , as well as against wound infections from facultative pathogens such as staphylococci or streptococci . More recently, the phage therapeutic approach has been applied to systemic and even intracellular infections, and non-replicating phage and isolated phage enzymes such as lysines have been added to the arsenal of antimicrobial agents. However, there is no actual evidence that these phage applications are effective in the field or in the clinic.

Western interest can in part be traced back to 1994, when Soothill demonstrated in animal models that phages can increase the success rate of skin grafts by reducing the underlying Pseudomonas aeruginosa infection . More recent studies have also substantiated these findings in the model system.

Even if it is not “phage therapy” in the original sense, the use of phages as transporters for conventional antibiotics represents another possible therapeutic application. The use of phages to transport anti-tumor agents in preliminary examinations on cells in tissue cultures has also been described.

Current and possible areas of application

Medical phage therapy

Treatment with bacteriophages is a possible alternative or supplement to conventional antibiotic therapies for bacterial infections.

Bacteriophages have a specific effect, because they only attack one or a few bacterial strains. Traditional antibiotics have a broader spectrum of activity and kill pathogenic bacteria as well as harmless or important ones, such as B. those that help with digestion. Phages can also be very effective against antibiotic-resistant bacteria. There are a number of recent publications that demonstrate the effectiveness of phages.

The Eliava Institute in Tbilisi, which has long been active in phage therapy, reports success rates between 67% for lung infections and up to 100% for inflammation of the bone marrow ( osteomyelitis ).

Some studies show that phages are able to migrate to a specific location - for example through the blood-brain barrier to the brain - and reproduce there using a suitable bacterial host. This mechanism has been shown to be effective in treating meningitis meningitis in a newborn. There are other publications on Pseudomonas aeruginosa , Klebsiella , Shigella , Staphylococci , Streptococci , Escherichia coli , Proteus , Salmonella and other germs. Laboratory tests showed that phage administered intraperitoneally , intravenously, or intranasally can kill bacteria .

Some pharmaceutical companies are currently (2014) developing phage enzymes, such as B. an endolysin against the methicillin-resistant Staphylococcus aureus (MRSA). They could be used in the form of impregnated wound dressings for the preventive treatment of burn victims, as well as phage-impregnated sutures.

Enzobiotics are a Rockefeller University development that creates enzymes from phages. These are able to prevent secondary infections with bacteria, such as those that can occur in patients with the flu, e.g. B. as pneumonia or otitis media . Purified enzymes from recombinant phages can be used as independent antibacterial agents.

Paul E. Turner's group is specifically looking for phages that counteract the resistance mechanism to antibiotics from Pseudomonas aeruginosa . In the USA, an infection with Pseudomonas aeruginosa was successfully treated with phage therapy.

In the Nuremberg Zoo, treatment with a phage cocktail from Tbilisi saved an Indian rhinoceros from being euthanized.

The EU- funded Phagoburn project was launched in 2013 to test the effectiveness of phages on burn wounds.

In Germany, phage therapy is one of the medical measures whose effect has not been proven and which is therefore not currently approved. According to Article 35 of the Declaration of Helsinki , it may therefore only be used in emergency situations and with the consent of the patient.

Phages have a specific effect on certain types of host . In many cases, it is therefore necessary to take a swab from the patient and start a bacterial culture from it before treatment can begin. A special phage cocktail is then mixed with this bacterial culture. In a phage cocktail there are always at least three precisely determined phages that act against the bacteria to be combated.

In practice, phages are topically applied to infected wounds or surfaces, infused, ingested orally, or used during surgical procedures. For topical application, the phages are often placed on gauze that is placed on the area to be treated.

In August 2006, the US FDA approved the spraying of phages into meat. Approval was granted for the preparation ListShield from the manufacturer Intralytix , a phage preparation that is effective against Listeria monocytogenes . It was the first approval of a phage-based food additive by the FDA and USDA . This initially raised concern because without labeling the consumer will not be aware that meat and poultry products have been treated with the agent. However, it confirms to the public that phages against Listeria are considered harmless in the global scientific community (approval as Generally Recognized As Safe ), and it opens the way for other phages to be GRAS approved.

Phage therapy has been tried on a wide variety of bacterial infections, including laryngitis , skin infections, dysentery , conjunctivitis , periodontitis , gingivitis , sinusitis , bacterial prostatitis , urinary tract and intestinal infections, burns , scalds , poly-microbial biofilms on chronic wounds, ulcers, and infected Surgical wounds .

In 2007, a clinical study of ear canal infections ( otitis ) with Pseudomonas aeruginosa was completed at the Royal London Ear, Nose and Throat Clinic . Documentation of the phase 1 / phase 2 study was published in August 2008 in the journal Clinical Otolaryngology .

Phase 1 clinical trials were conducted in 2009 at the Southwest Regional Wound Care Center in Lubbock, Texas on an approved cocktail of antibacterial phage. This acts u. a. against Pseudomonas aeruginosa , Staphylococcus aureus and Escherichia coli . The phage cocktail was produced and made available by the Intralytix company in Baltimore, Maryland. In 2019 it is reported that a patient who was infected with a multi-resistant bacterium was successfully treated in London. The Great Ormond Street Hospital worked with the University of Pittsburgh together. Effective phages were identified, but also had to be genetically modified to increase their effectiveness; the patient recovered almost completely.

Review articles on phage therapy suggest that more clinical and microbiological research is required to meet current regulatory standards.

Because of the specificity of the phages, phage therapy with a cocktail would be an obvious choice, but this is fundamentally rejected by the American Food and Drug Administration . Researchers and observers suggest that the FDA must change its position on drug cocktails for phage therapy to work. In the general public, knowledge about phage therapy is limited to those working in research and is rarely found in the mass media. The negative image attached to viruses in the public consciousness may also be responsible for the reluctance with which phage therapy is treated.

It has been known for over 30 years that mycobacteria such as Mycobacterium tuberculosis have specific bacteriophages. No lytic phage has yet been discovered for Clostridium difficile , which is responsible for many nosocomial infections . But some temperate (i.e. genome- integrated) phages are known for this species, which opens up promising avenues.

Therapeutic effectiveness

The George Eliava Institute in Tbilisi has been collecting bacteriophages and performing phage therapy for 100 years. Depending on the bacterial infection, phage cocktails with a therapeutic effectiveness of up to 100% were achieved.

The Ludwik Hirszfeld Institute in Wrocław also offers phage therapy. There are many publications about the therapeutic efficacy , just as there are from Tbilisi.

In Russia, mixed phage preparations are said to have shown a therapeutic effectiveness of 50%.

safety

Problems with phage therapy can mainly be caused by the superspreaders (phages with pronounced horizontal gene exchange), whereby the controlled application in humans is less problematic than the large-scale application in the agricultural and food industry. In the stables, an unmanageable number of new resistance genes are being bred through the abuse of antibiotics . These can be well distributed and maintained by the super spreaders.

As with antibiotic treatment and other methods of combating bacterial infections, some bacteria release endotoxins in the patient when they are destroyed ( Jarisch-Herxheimer reaction ). This can cause fever symptoms . In extreme cases, toxic shock syndrome is possible (a risk that also exists with antibiotics).

One way of avoiding this problem has been suggested by Janakiraman Ramachandran, formerly at AstraZeneca India, where he founded GangaGen, a phage therapy startup in Bangladesh: Genetically modified bacteriophages could be used for those types of infections that are likely to have this reaction in which the gene for producing endolysin is removed. Without this gene, the host bacterium also dies, but since there is no lysis, its shell remains intact. However, this modification also prevents the phages from multiplying exponentially, so that an administered phage means a dead bacterial cell. These dead cells are finally destroyed in the course of normal “house cleaning” by the phagocytes , which break down the bacterium and its interior into harmless proteins, polysaccharides and lipids using enzymes.

Temperate bacteriophages are normally not used therapeutically, as some of these phages also transfer bacterial DNA from one host cell to the next, which means that antibiotic resistance spreads and bacteria can theoretically even become pathogenic (see cholera ).

Use of phages in fruit and vegetable cultivation

Phages have long been discussed for use against harmful bacteria in fruit and vegetable cultivation. There are publications on the use against Erwinia amylovora , Pseudomonas , Xanthomonas , Streptomyces , Pectobacterium carotovorum , Xylella fastidiosa , Ralstonia solanacearum , Dickeya solani and Pectobacterium .

At the Brigham Young University is researching the use of phage therapy for the treatment of American foulbrood in bees.

Technical aspects

Obtaining the phage

The basic principle of phage production is to take samples from the place where a large number of the corresponding bacteria are likely to be found. Samples can be obtained from wastewater, in rivers, in lakes or from the ground. The samples taken are examined for the phages sought. For this purpose, the aqueous solution is sterile-filtered . Since phages are much smaller than bacteria, the bacteria remain in the filter and the phages go into solution. The mixture of particles smaller than 0.45 µm can then be examined. This takes place on an appropriate nutrient medium on which the bacteria to be examined have been cultivated . Suitable phages form plaques on the bacterial lawn , which are caused by the dead bacteria. The phages can then be enriched and examined.

Good manufacturing practice is important when examining the phage . This means that in the end there is only one single, precisely defined phage. This phage is then mixed with other phages to produce a phage cocktail.

Also because of their high specificity, a mixture of phages is often used in order to achieve a high probability of success. This means that phage banks must be maintained and regularly refreshed with new phages.

Stability of phages and phage preparations

The stability of phages during storage and transport differ depending on the phage. There are different families of bacteriophages and their sensitivity to external factors such as temperature, exposure to acids, salt concentration and UV radiation is very different.

Some phages need to be kept cool, while others do not.

The pH value is important for the stability of all phages . It can be set to be stable with buffer solutions . Some phages can be freeze-dried and processed into oral dosage forms without significantly impairing their effectiveness.

Gene transfer

It has been known since at least 1962 that phages can exchange genes horizontally . Even today there are always scientific reports that phages can also transfer antibiotic resistance from one bacterium to another. There are also reports about so-called “super spreaders”, these are phages that carry out the horizontal gene exchange very extensively. Such superspreaders should be avoided at all costs during phage therapy. That is why many scientists today are calling for good manufacturing practice for phage cocktails. Furthermore, with regard to this aspect, the use of phages in the agro-food industry must be viewed critically.

A research group from the Weizmann Institute was able to show that special phages that infect Bacillus can switch between the lysogenic and lytic cycle with a small peptide over 6 amino acids . The research group named the type of communication with Arbitrium system . This means that phage interact with the bacteria in two ways. They either pop the host or invade and integrate into the host's genome and wait. For phage therapy one would have to make sure that the lysogenic cycle does not occur first .

Phage banks

The need to maintain phage banks makes regulatory safety testing more difficult and expensive. This would make it difficult to manufacture phage therapeutic products on a large scale. Patent law issues (especially with regard to living organisms) could make distribution difficult for companies that want exclusive rights to their "invention".

Phage resistance

As with antibiotics, bacteria can against the treatment resistant are. In this case they survive the attack of the phages through mutations . However, evolution quickly produces new phage types that can destroy the bacteria that have become resistant. In addition, bacteria that have become resistant to phages often lose their virulence significantly or in this process otherwise partially or completely lose their danger to humans or animals. This is due to the conversion processes of the bacterial shell as a defense measure in the development of resistance to phages, which u. a. can lead to the human immune system being able to better recognize and / or attack the bacteria. When phages are injected into the bloodstream, they are recognized by the human immune system. Some of these are cleared quickly and, after a period of time, antibodies to the phage are produced. It seems that for this reason a given phage can only be used once for intravenous treatment.

See also

literature

Web links

Individual evidence

  1. ^ McAuliffe et al: The New Phage Biology: From Genomics to Applications. (introduction) In: S. Mc Grath, D. van Sinderen (Eds.): Bacteriophage: Genetics and Molecular Biology. Caister Academic Press, Norfolk UK 2007, ISBN 978-1-904455-14-1 . (reprint)
  2. ↑ a b Phage - The Virus that Cures . (Video, 49 min.) BBC Horizon, October 9, 1997.
  3. ^ T. Parfitt: Georgia: an unlikely stronghold for bacteriophage therapy . In: The Lancet . tape 365 , no. 9478 , 2005, p. 2166-2167 , doi : 10.1016 / S0140-6736 (05) 66759-1 , PMID 15986542 .
  4. ^ A b Karl Thiel: Old dogma, new tricks - 21st Century phage therapy . In: Nature Biotechnology . tape 22 , no. 1 . London UK January 2004, p. 31-36 , doi : 10.1038 / nbt0104-31 , PMID 14704699 ( nature.com [accessed December 15, 2007]).
  5. ↑ Maria Aguita: Combating Bacterial Infection. LabNews.co.uk, accessed May 5, 2009 .
  6. ↑ Rebekah M. Dedrick, Carlos A. Guerrero-Bustamante, Rebecca A. Garlena, Daniel A. Russell, Katrina Ford, Kathryn Harris, Kimberly C. Gilmour, James Soothill, Deborah Jacobs-Sera, Robert T. Schooley, Graham F. Hatfull, Helen Spencer: Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus , in: Nat Med 25, pp. 730-733, May 8, 2019, doi: 10.1038 / s41591-019-0437-z . Free author manuscript of November 8, 2019, PMC 6557439 (free full text), PMID 31068712 . ResearchGate
  7. ↑ [1] , on: Howard Hughes Medical Institute, May 8, 2019
  8. ↑ Sascha Karberg: Heilsame bacteria eaters , on: tagesspiegel.de of May 9, 2019
  9. ^ Daniel Bojar: Useful bacteria killers , Spectrum of Science, June 2020, pp. 40–45
  10. ↑ A. Pirisi: Phage therapy - advantages over antibiotics? In: Lancet . tape 356 , no. 9239 , 2000, pp. 1418 , doi : 10.1016 / S0140-6736 (05) 74059-9 , PMID 11052592 .
  11. ↑ B. Hofer: Conservation with viruses. Heise, February 28, 2013, accessed May 15, 2013 .
  12. ↑ SM Shasha, N. Sharon, M. Inbar: [Bacteriophages as antibacterial agents] . In: Harefuah . tape 143 , no. 2 , 2004, p. 121-125, 166 , PMID 15143702 (Hebrew).
  13. ↑ GW Hanlon: Bacteriophages: an appraisal of their role in the treatment of bacterial infections . In: Int J Antimicrob Agents . tape 30 , no. 2 , 2007, p. 118-28 , doi : 10.1016 / j.ijantimicag.2007.04.006 , PMID 17566713 ( elsevier.com ).
  14. ↑ Stalin's Forgotten Cure. In: Science . Volume 298, October 25, 2002, pp. 728-731. (PDF; 285 kB)
  15. ^ WC Summers: Bacteriophage therapy . In: Annu. Rev. Microbiol . tape 55 , 2001, p. 437-451 , doi : 10.1146 / annurev.micro.55.1.437 , PMID 11544363 .
  16. ↑ Nina Chanishvili: A Literature Review of the Practical Application of Bacteriophage Research. Nova Science, New York 2011, ISBN 978-1-62100-851-4 .
  17. ↑ MJ Mangen, AH Havelaar, KP Poppe, GA de Wit: Cost-utility analysis to control Campylobacter on chicken meat: dealing with data limitations . In: Risk Anal . tape 27 , no. 4 , 2007, p. 815-830 , doi : 10.1111 / j.1539-6924.2007.00925.x , PMID 17958494 .
  18. ↑ S. Mc Grath, D. van Sinderen (Ed.): Bacteriophage: Genetics and Molecular Biology . 1st edition. Caister Academic Press, 2007, ISBN 978-1-904455-14-1 ( horizonpress.com ).
  19. ↑ JS Soothill: Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa . In: Burns . tape 20 , no. 3 , 1994, p. 209-211 , doi : 10.1016 / 0305-4179 (94) 90184-8 , PMID 8054131 .
  20. ↑ CS McVay, M. Velásquez, JA Fralick: Phage therapy of Pseudomonas aeruginosa infection in a mouse burn wound model . In: Antimicrob Agents Chemother . tape 51 , no. 6 , 2007, p. 1934–1938 , doi : 10.1128 / AAC.01028-06 , PMID 17387151 , PMC 1891379 (free full text).
  21. ↑ I. Yacoby, H. Bar, I. Benhar: Targeted drug-carrying Bacteriophages as antibacterial nano medicines . In: Antimicrob. Agents Chemother . tape 51 , no. 6 , 2007, p. 2156-2163 , doi : 10.1128 / AAC.00163-07 , PMID 17404004 , PMC 1891362 (free full text).
  22. ↑ I. Yacoby, M. Shamis, H. Bar, D. Shabat, I. Benhar: Targeting antibacterial agents by using drug-carrying filamentous Bacteriophages . In: Antimicrob. Agents Chemother . tape 50 , no. 6 , 2006, p. 2087-2097 , doi : 10.1128 / AAC.00169-06 , PMID 16723570 , PMC 1479106 (free full text).
  23. ↑ H. Bar, I. Yacoby, I. Benhar: Killing cancer cells by targeted drug-carrying phage nanomedicines . In: BMC Biotechnol . tape 8 , 2008, p. 37 , doi : 10.1186 / 1472-6750-8-37 , PMID 18387177 , PMC 2323368 (free full text) - ( biomedcentral.com ).
  24. ↑ A. Górski, R. Miedzybrodzki, J. Borysowski, B. Weber-Dabrowska, M. Lobocka, W. Fortuna, S. Letkiewicz, M. Zimecki, G. Filby: Bacteriophage therapy for the treatment of infections . In: Current Opinion in Investigational Drugs . tape 10 , no. 8 , August 2009, p. 766-74 , PMID 19649921 .
  25. ↑ DH Duckworth, PA Gulig: Bacteriophages: potential treatment for bacterial infections . In: BioDrugs . tape 16 , no. 1 , 2002, p. 57-62 , PMID 11909002 .
  26. ↑ Ryszard Międzybrodzki, Jan Borysowski, Beata Weber-Dąbrowska, Wojciech Fortuna, Sławomir Letkiewicz: Chapter 3 - Clinical Aspects of Phage Therapy . In: Advances in Virus Research (=  Bacteriophages, Part B ). tape 83 . Academic Press, January 1, 2012, p. 73–121 ( sciencedirect.com [accessed February 6, 2017]).
  27. ↑ Mzia Kutateladze, Revaz Adamia: Bacteriophages as potential new therapeutics to replace or supplement antibiotics . In: Trends in Biotechnology . tape 28 , no. 12 , December 1, 2010, p. 591-595 , doi : 10.1016 / j.tibtech.2010.08.001 ( sciencedirect.com [accessed February 6, 2017]).
  28. ↑ L. Strój, B. Weber-Dabrowska, K. Partyka, M. Mulczyk, M. Wójcik: [Successful treatment with bacteriophage in purulent cerebrospinal meningitis in a newborn]. In: Neurologia i neurochirurgia polska . tape 33 , no. 3 , January 1, 1999, ISSN  0028-3843 ( europepmc.org [accessed February 6, 2017]).
  29. ↑ Victor Krylov, Olga Shaburova, Elena Pleteneva, Maria Bourkaltseva, Sergey Krylov: Modular Approach to Select Bacteriophages Targeting Pseudomonas aeruginosa for Their Application to Children Suffering With Cystic Fibrosis . In: Antimicrobials, Resistance and Chemotherapy . January 1, 2016, p. 1631 , doi : 10.3389 / fmicb.2016.01631 , PMID 27790211 , PMC 5062033 (free full text) - ( journal.frontiersin.org [accessed February 6, 2017]).
  30. ↑ Alexander Sulakvelidze, Zemphira Alavidze, J. Glenn Morris: Bacteriophage Therapy . In: Antimicrobial Agents and Chemotherapy . tape 45 , no. 3 , March 1, 2001, ISSN  0066-4804 , p. 649-659 , doi : 10.1128 / AAC.45.3.649-659.2001 , PMID 11181338 , PMC 90351 (free full text) - ( aac.asm.org [accessed February 6, 2017]).
  31. ↑ GG Bogovazova, NN Voroshilova, VM Bondarenko: [The efficacy of Klebsiella pneumoniae bacteriophage in the therapy of experimental Klebsiella infection] . In: Zhurnal Mikrobiologii, Epidemiologii, I Immunobiologii . No. 4 , ISSN  0372-9311 , p. 5-8 , PMID 1882608 .
  32. ↑ Dutch biotech company Micreos launches the first bactericidal enzyme for the treatment of MRSA in humans . In: wallstreet-online.de . November 6, 2014 ( wallstreet-online.de [accessed February 6, 2017]).
  33. ^ Scientists Engineer Viruses To Battle Bacteria. March 6, 2009.
  34. ↑ J. Borysowski, B. Weber-Dabrowska, A. Górski: Bacteriophage endolysins as a novel class of antibacterial agents . In: Experimental Biology and Medicine (Maywood NJ) . tape 231 , no. 4 , 2006, p. 366-377 , PMID 16565432 .
  35. ↑ Benjamin K. Chan, Mark Sistrom, John E. Wertz, Kaitlyn E. Kortright, Deepak Narayan: Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa . In: Scientific Reports . tape 6 , May 26, 2016, ISSN  2045-2322 , doi : 10.1038 / srep26717 , PMID 27225966 ( nature.com [accessed February 7, 2017]).
  36. ↑ A virus, fished out of a lake, may have saved a man's life. December 7, 2016, accessed February 6, 2017 .
  37. ↑ Saved from euthanasia: Phage therapy supports Nuremberg rhinoceros in healing . In: MEDICINE ASPECTS . November 8, 2016 ( Medizin-aspekte.de [accessed February 6, 2017]).
  38. ↑ Phagoburn European Research & Development (R&D) project , accessed on August 7, 2017.
  39. ^ Declaration of Helsinki - Ethical principles for medical research on humans. ( Memento of November 13, 2012 in the Internet Archive ) World Medical Association, 2008.
  40. ↑ Use of unproven measures ( Memento from September 20, 2012 in the Internet Archive )
  41. ↑ FDA says viruses safe for treating meat
  42. ↑ Pathogen eradication by phage therapy in patients with chronic bacterial prostatitis. ( Memento from October 23, 2014 in the Internet Archive )
  43. ↑ BC Capital secures £ 500,000 funding for Biocontrol Limited to further the development of its successful phage therapy. ( Memento from April 14, 2009 in the Internet Archive )
  44. ^ Sourcing Development Funding: Biocontrol - Southampton Television documentary. Archived from the original on April 15, 2009 ; Retrieved December 13, 2007 .
  45. ^ Scientists start germ warfare to beat illness. - biocontrol-ltd.com. Archived from the original on April 13, 2009 ; Retrieved April 30, 2008 .
  46. ↑ A. Wright, CH Hawkins, EE Änggård, DR Harper: A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. In: Clinical Otolaryngology. Volume 34, No. 4, 2009, pp. 349-357. doi : 10.1111 / j.1749-4486.2009.01973.x .
  47. ↑ DD Rhoads, RD Wolcott et al: Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. In: J Wound Care. June 2009, Vol. 18, No. 6, pp. 237-238, 240-243.
  48. ↑ Teenager recovers from near death in world-first GM virus treatment , article in The Guardian of May 8, 2019 (link checked May 9, 2019).
  49. ↑ Harald Brüssow: Phage therapy: the Escherichia coli experience. In: Microbiology. Volume 151, No. 7S, July 2005, S, 2133–2140, doi: 10.1099 / mic.0.27849-0 , (full text) ( Memento from May 26, 2011 in the Internet Archive )
  50. ↑ Agata Anna Cisek, Iwona Dąbrowska, Karolina Paulina Gregorczyk, Zbigniew Wyżewski: Phage Therapy in Bacterial Infections Treatment: One Hundred Years After the Discovery of Bacteriophages . In: Current Microbiology . tape 74 , no. 2 , November 28, 2016, ISSN  0343-8651 , p. 277–283 , doi : 10.1007 / s00284-016-1166-x , PMID 27896482 ( springer.com [accessed February 8, 2017]).
  51. ^ K. Thiel: Old dogma, new tricks - 21st century phage therapy . In: Nat. Biotechnol. tape 22 , no. 1 , 2004, p. 31-36 , doi : 10.1038 / nbt0104-31 , PMID 14704699 .
  52. ^ H. Brüssow: Phage Therapy: The Western Perspective. In: Stephen Mc Grath, Douwe van Sinderen: Bacteriophage: Genetics and Molecular Biology. Caister Academic Press, Norfolk UK 2007, ISBN 978-1-904455-14-1 .
  53. ↑ G. Verbeken, D. De Vos, M. Vaneechoutte, M. Merabishvili, M. Zizi, JP Pirnay: European regulatory conundrum of phage therapy . In: Future Microbiol . tape 2 , no. 5 , 2007, p. 485-491 , doi : 10.2217 / 17460913.2.5.485 , PMID 17927471 .
  54. ↑ Graham F. Hatfull: Mycobacteriophages: Pathogenesis and Applications. In: Matthew K Waldor, David I Friedman, Sankar Lal Adhya: Phages: Their role in bacterial pathogenesis and biotechnology. ASM Press, Washington DC 2005, ISBN 1-55581-307-0 , pp. 238-255.
  55. ↑ Mzia Kutateladze, Revaz Adamia: Bacteriophages as potential new therapeutics to replace or supplement antibiotics . In: Trends in Biotechnology . tape 28 , no. 12 , 2010, p. 591-595 , doi : 10.1016 / j.tibtech.2010.08.001 ( elsevier.com ).
  56. ↑ EC Keen, SL Adhya: Phage Therapy: Current Research and Applications . In: Clinical Infectious Diseases . tape 61 , no. 1 , July 1, 2015, ISSN  1058-4838 , p. 141–142 , doi : 10.1093 / cid / civ257 ( oup.com [accessed February 15, 2017]).
  57. ↑ Article in Russian . (PDF) On: files.school-collection.edu.ru ; Retrieved April 9, 2014.
  58. ↑ Eric C. Keen, Valery V. Bliskovsky, Francisco Malagon, James D. Baker, Jeffrey S. Prince: Novel “Superspreader” Bacteriophages Promote Horizontal Gene Transfer by Transformation . In: mBio . tape 8 , no. 1 , ISSN  2150-7511 , p. e02115 – e02116 , doi : 10.1128 / mBio.02115-16 , PMID 28096488 ( asm.org [accessed February 15, 2017]).
  59. ↑ Evergreen Phage Biology and Phage Therapy ( Memento of March 2, 2007 in the Internet Archive ). In: evergreen.edu , accessed on April 9, 2014.
  60. ↑ Stuart Ira Fox: Human Physiology . 6th edition. McGraw-Hill, 1999, ISBN 0-697-34191-7 , pp. 50, 55, 448, 449 .
  61. ↑ Colin Buttimer, Olivia McAuliffe, RP Ross, Colin Hill, Jim O'Mahony: Bacteriophages and Bacterial Plant Diseases . In: Antimicrobials, Resistance and Chemotherapy . January 1, 2017, p. 34 , doi : 10.3389 / fmicb.2017.00034 ( frontiersin.org [accessed February 7, 2017]).
  62. ↑ Bee Killers: Using Phages Against Deadly Honeybee Diseases on YouTube, accessed June 5, 2016.
  63. ↑ Using microscopic bugs to save the bees on the Brigham Young University website, accessed June 5, 2016.
  64. ↑ E. Jończyk M. Kłak, R. Międzybrodzki, A. Górski: The influence of external factors on Bacteriophages-review . In: Folia Microbiologica . tape 56 , no. 3 , May 31, 2011, ISSN  0015-5632 , p. 191-200 , doi : 10.1007 / s12223-011-0039-8 , PMID 21625877 , PMC 3131515 (free full text) - ( link.springer.com [accessed February 10, 2017]).
  65. ↑ JP Collman: Naturally Dangerous: Surprising facts about food, health, and the environment. University Press, Sausalito CA 2001, p. 92.
  66. ↑ E. Jończyk M. Kłak, R. Międzybrodzki, A. Górski: The influence of external factors on Bacteriophages-review . In: Folia Microbiologica . tape 56 , no. 3 , May 31, 2011, ISSN  0015-5632 , p. 191-200 , doi : 10.1007 / s12223-011-0039-8 , PMID 21625877 , PMC 3131515 (free full text) - ( springer.com [accessed February 6, 2017]).
  67. ^ Barter with hereditary traits . In: The time . February 23, 1962, ISSN  0044-2070 ( zeit.de [accessed February 6, 2017]).
  68. ↑ Amira Shousha, Nattakarn Awaiwanont, Dmitrij Sofka, Frans JM Smulders, Peter Paulsen: Bacteriophages Isolated from Chicken Meat and the Horizontal Transfer of Antimicrobial Resistance Genes . In: Applied and Environmental Microbiology . tape 81 , no. 14 , July 15, 2015, ISSN  0099-2240 , p. 4600-4606 , doi : 10.1128 / AEM.00872-15 , PMID 25934615 , PMC 4551174 (free full text) - ( asm.org [accessed February 6, 2017]).
  69. ↑ Eric C. Keen, Valery V. Bliskovsky, Francisco Malagon, James D. Baker, Jeffrey S. Prince: Novel “Superspreader” Bacteriophages Promote Horizontal Gene Transfer by Transformation . In: mBio . tape 8 , no. 1 , January 17, 2017, ISSN  2150-7511 , p. e02115 – e02116 , doi : 10.1128 / mBio.02115-16 , PMID 28096488 , PMC 5241400 (free full text) - ( asm.org [accessed February 6, 2017]).
  70. ↑ Zohar Erez, Ida Steinberger-Levy, Maya Shamir, Shany Doron, Avigail Stokar-Avihail: Communication between viruses guides lysis – lysogeny decisions . In: Nature . tape 541 , no. 7638 , p. 488-493 , doi : 10.1038 / nature21049 ( nature.com ).
  71. ↑ Thomas Häusler: The advantages and disadvantages of phage therapy. In: Binturong. Accessed May 17, 2019 .