Editing Bacteriophage (section)

==Uses==
=== Phage therapy ===
{{Main|Phage therapy}}

[[File:George Eliava 1892–1937.jpg|right|thumb|upright|[[George Eliava]] pioneered the use of phages in treating bacterial infections]]

Phages were discovered to be antibacterial agents and were used in the former [[Soviet]] Republic of [[Georgia (country)|Georgia]] (pioneered there by [[Giorgi Eliava]] with help from the co-discoverer of bacteriophages, [[Félix d'Hérelle]]) during the 1920s and 1930s for treating bacterial infections.

D'Herelle "quickly learned that bacteriophages are found wherever bacteria thrive: in sewers, in rivers that catch waste runoff from pipes, and in the stools of convalescent patients."<ref>{{Citation | vauthors = Kuchment A | year = 2012 | title = The Forgotten Cure: The past and future of phage therapy | publisher = Springer | page  = 11 | isbn = 978-1-4614-0250-3 }}</ref>

They had widespread use, including treatment of soldiers in the [[Red Army]].<ref>{{cite journal | vauthors = Myelnikov D | title = An Alternative Cure: The Adoption and Survival of Bacteriophage Therapy in the USSR, 1922-1955 | journal = Journal of the History of Medicine and Allied Sciences | volume = 73 | issue = 4 | pages = 385–411 | date = October 2018 | pmid = 30312428 | pmc = 6203130 | doi = 10.1093/jhmas/jry024 }}</ref> However, they were abandoned for general use in the West for several reasons:
* Antibiotics were discovered and marketed widely. They were easier to make, store, and prescribe.
* Medical trials of phages were carried out, but a basic lack of understanding of phages raised questions about the validity of these trials.<ref>{{cite journal | vauthors = Kutter E, De Vos D, Gvasalia G, Alavidze Z, Gogokhia L, Kuhl S, Abedon ST | title = Phage therapy in clinical practice: treatment of human infections | journal = Current Pharmaceutical Biotechnology | volume = 11 | issue = 1 | pages = 69–86 | date = January 2010 | pmid = 20214609 | doi = 10.2174/138920110790725401 | s2cid = 31626252 }}</ref>
* Publication of research in the Soviet Union was mainly in the [[Russian language|Russian]] or [[Georgian language]]s and for many years was not followed internationally.
* The Soviet technology was widely discouraged and in some cases illegal due to the [[red scare]].

The use of phages has continued since the end of the [[Cold War]] in Russia,<ref name="Gol">{{cite journal | vauthors = Golovin S | url = https://www.nkj.ru/archive/articles/31498/ | title = Бактериофаги: убийцы в роли спасителей | trans-title = Bacteriophages: killers as saviors | language = Russian | journal = [[Наука и жизнь]] | trans-journal = Nauka I Zhizn (Science and life) | date = 2017 | issue = 6 | pages = 26–33 }}</ref> Georgia, and elsewhere in Central and Eastern Europe. The first regulated, randomized, double-blind [[clinical trial]] was reported in the ''Journal of Wound Care'' in June 2009, which evaluated the safety and efficacy of a bacteriophage cocktail to treat infected venous ulcers of the leg in human patients.<ref name="Rhoads2009">{{cite journal | vauthors = Rhoads DD, Wolcott RD, Kuskowski MA, Wolcott BM, Ward LS, Sulakvelidze A | title = Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial | journal = Journal of Wound Care | volume = 18 | issue = 6 | pages = 237–8, 240–3 | date = June 2009 | pmid = 19661847 | doi = 10.12968/jowc.2009.18.6.42801 }}</ref> The FDA approved the study as a Phase I clinical trial. The study's results demonstrated the safety of therapeutic application of bacteriophages, but did not show efficacy. The authors explained that the use of certain chemicals that are part of standard wound care (e.g. [[lactoferrin]] or silver) may have interfered with bacteriophage viability.<ref name="Rhoads2009" /> Shortly after that, another controlled clinical trial in Western Europe (treatment of ear infections caused by ''Pseudomonas aeruginosa'') was reported in the journal ''[[Clinical Otolaryngology]]'' in August 2009.<ref name="Wright2009">{{cite journal | vauthors = Wright A, Hawkins CH, Anggård EE, Harper DR | title = A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy | journal = Clinical Otolaryngology | volume = 34 | issue = 4 | pages = 349–357 | date = August 2009 | pmid = 19673983 | doi = 10.1111/j.1749-4486.2009.01973.x | doi-access = free }}</ref> The study concludes that bacteriophage preparations were safe and effective for treatment of chronic ear infections in humans. Additionally, there have been numerous animal and other experimental clinical trials evaluating the efficacy of bacteriophages for various diseases, such as infected burns and wounds, and cystic fibrosis-associated lung infections, among others.<ref name="Wright2009"/> On the other hand, phages of ''[[Inoviridae]]'' have been shown to complicate [[biofilms]] involved in [[pneumonia]] and [[cystic fibrosis]] and to shelter the bacteria from drugs meant to eradicate disease, thus promoting persistent infection.<ref>{{cite journal | vauthors = Sweere JM, Van Belleghem JD, Ishak H, Bach MS, Popescu M, Sunkari V, Kaber G, Manasherob R, Suh GA, Cao X, de Vries CR, Lam DN, Marshall PL, Birukova M, Katznelson E, Lazzareschi DV, Balaji S, Keswani SG, Hawn TR, Secor PR, Bollyky PL | title = Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection | journal = Science | volume = 363 | issue = 6434 | pages = eaat9691 | date = March 2019 | pmid = 30923196 | pmc = 6656896 | doi = 10.1126/science.aat9691 | doi-access = free }}</ref>

Meanwhile, bacteriophage researchers have been developing engineered viruses to overcome [[antimicrobial resistance|antibiotic resistance]], and engineering the phage genes responsible for coding enzymes that degrade the biofilm matrix, phage structural proteins, and the enzymes responsible for [[lysis]] of the bacterial cell wall.<ref name="mmbr"/><ref name="Prescott"/><ref name="horizon"/> There have been results showing that T4 phages that are small in size and short-tailed can be helpful in detecting ''E. coli'' in the human body.<ref>{{cite journal | vauthors = Tawil N, Sacher E, Mandeville R, Meunier M | title = Surface plasmon resonance detection of E. coli and methicillin-resistant S. aureus using bacteriophages | journal = Biosensors & Bioelectronics | volume = 37 | issue = 1 | pages = 24–29 | date = May 2012 | pmid = 22609555 | doi = 10.1016/j.bios.2012.04.048 | url = https://lp2l.polymtl.ca/sites/default/files/Articles/2012-Tawil.pdf | url-status = live | archive-url = https://web.archive.org/web/20230202231339/https://lp2l.polymtl.ca/sites/default/files/Articles/2012-Tawil.pdf | archive-date = 2023-02-02 }}</ref>

Therapeutic efficacy of a phage cocktail was evaluated in a mouse model with nasal infection of multi-drug-resistant (MDR) ''[[A. baumannii]]''. Mice treated with the phage cocktail showed a 2.3-fold higher survival rate compared to those untreated at seven days post-infection.<ref>{{cite journal | vauthors = Cha K, Oh HK, Jang JY, Jo Y, Kim WK, Ha GU, Ko KS, Myung H | title = Characterization of Two Novel Bacteriophages Infecting Multidrug-Resistant (MDR) ''Acinetobacter baumannii'' and Evaluation of Their Therapeutic Efficacy ''in Vivo'' | journal = Frontiers in Microbiology | volume = 9 | page = 696 | date = 10 April 2018 | pmid = 29755420 | pmc = 5932359 | doi = 10.3389/fmicb.2018.00696 | doi-access = free }}</ref>

In 2017, a 68-year-old diabetic patient with necrotizing pancreatitis complicated by a pseudocyst infected with MDR ''A. baumannii'' strains was being treated with a cocktail of Azithromycin, Rifampicin, and Colistin for 4 months without results and overall rapidly declining health.

Because discussion had begun of the clinical futility of further treatment, an Emergency Investigational New Drug (eIND) was filed as a last effort to at the very least gain valuable medical data from the situation, and approved, so he was subjected to phage therapy using a percutaneously (PC) injected cocktail containing nine different phages that had been identified as effective against the primary infection strain by rapid isolation and testing techniques (a process which took under a day). This proved effective for a very brief period, although the patient remained unresponsive and his health continued to worsen; soon isolates of a strain of ''A. baumannii'' were being collected from drainage of the cyst that showed resistance to this cocktail, and a second cocktail which was tested to be effective against this new strain was added, this time by intravenous (IV) injection as it had become clear that the infection was more pervasive than originally thought.<ref name="PhageCockt2017"/>

Once on the combination of the IV and PC therapy the patient's downward clinical trajectory reversed, and within two days he had awoken from his coma and become responsive. As his immune system began to function he had to be temporarily removed from the cocktail because his fever was spiking to over {{convert|104|F|C}}, but after two days the phage cocktails were re-introduced at levels he was able to tolerate. The original three-antibiotic cocktail was replaced by minocycline after the bacterial strain was found not to be resistant to this and he rapidly regained full lucidity, although he was not discharged from the hospital until roughly 145 days after phage therapy began. Towards the end of the therapy it was discovered that the bacteria had become resistant to both of the original phage cocktails, but they were continued because they seemed to be preventing minocycline resistance from developing in the bacterial samples collected so were having a useful synergistic effect.<ref name="PhageCockt2017">{{cite journal | vauthors = Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, Barr JJ, Reed SL, Rohwer F, Benler S, Segall AM, Taplitz R, Smith DM, Kerr K, Kumaraswamy M, Nizet V, Lin L, McCauley MD, Strathdee SA, Benson CA, Pope RK, Leroux BM, Picel AC, Mateczun AJ, Cilwa KE, Regeimbal JM, Estrella LA, Wolfe DM, Henry MS, Quinones J, Salka S, Bishop-Lilly KA, Young R, Hamilton T | title = Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection | journal = Antimicrobial Agents and Chemotherapy | volume = 61 | issue = 10 | date = October 2017 | pmid = 28807909 | pmc = 5610518 | doi = 10.1128/AAC.00954-17 }}</ref>

=== Other ===
====Food industry====
Phages have increasingly been used to safen food products and to forestall [[spoilage bacteria]].<ref name="OSullivan-et-al-2019">{{cite journal | vauthors = O'Sullivan L, Bolton D, McAuliffe O, Coffey A | title = Bacteriophages in Food Applications: From Foe to Friend | journal = Annual Review of Food Science and Technology | volume = 10 | issue = 1 | pages = 151–172 | date = March 2019 | pmid = 30633564 | doi = 10.1146/annurev-food-032818-121747 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | s2cid = 58620015 }}</ref> Since 2006, the [[United States Food and Drug Administration]] (FDA) and [[United States Department of Agriculture]] (USDA) have approved several bacteriophage products. LMP-102 (Intralytix) was approved for treating ready-to-eat (RTE) poultry and meat products. In that same year, the FDA approved LISTEX (developed and produced by [[Micreos (company)|Micreos]]) using bacteriophages on cheese to kill ''[[Listeria monocytogenes]]'' bacteria, in order to give them [[generally recognized as safe]] (GRAS) status.<ref>U.S. FDA/CFSAN: Agency Response Letter, GRAS Notice No. 000198</ref> In July 2007, the same bacteriophage were approved for use on all food products.<ref>(U.S. FDA/CFSAN: Agency Response Letter, GRAS Notice No. 000218)</ref> In 2011 USDA confirmed that LISTEX is a clean label processing aid and is included in USDA.<ref>{{cite web | url = http://www.fsis.usda.gov/oppde/rdad/fsisdirectives/7120.1.pdf | title = FSIS Directive 7120: Safe and Suitable Ingredients Used in the Production of Meat, Poultry, and Egg Products | publisher = United States Department of Agriculture | work = Food Safety and Inspection Service | location = Washington, DC | archive-url = https://web.archive.org/web/20111018071043/http://www.fsis.usda.gov/OPPDE/rdad/FSISDirectives/7120.1.pdf | archive-date = 18 October 2011 }}</ref> Research in the field of food safety is continuing to see if lytic phages are a viable option to control other food-borne pathogens in various food products.<ref>{{cite journal | vauthors = Khan FM, Chen JH, Zhang R, Liu B | title = A comprehensive review of the applications of bacteriophage-derived endolysins for foodborne bacterial pathogens and food safety: recent advances, challenges, and future perspective | journal = Frontiers in Microbiology | volume = 14 | page = 1259210 | date = 2023 | pmid = 37869651 | pmc = 10588457 | doi = 10.3389/fmicb.2023.1259210 | doi-access = free }}</ref>

====Water indicators====
Bacteriophages, including those specific to ''Escherichia coli'', have been employed as indicators of fecal contamination in water sources. Due to their shared structural and biological characteristics, coliphages can serve as proxies for viral fecal contamination and the presence of pathogenic viruses such as rotavirus, norovirus, and HAV. Research conducted on wastewater treatment systems has revealed significant disparities in the behavior of coliphages compared to fecal coliforms, demonstrating a distinct correlation with the recovery of pathogenic viruses at the treatment's conclusion. Establishing a secure discharge threshold, studies have determined that discharges below 3000 PFU/100 mL are considered safe in terms of limiting the release of pathogenic viruses.<ref>Chacón L, Barrantes K, Santamaría-Ulloa C, Solano MReyes L, Taylor LValiente C, Symonds EM, Achí R. 2020. A Somatic Coliphage Threshold Approach To Improve the Management of Activated Sludge Wastewater Treatment Plant Effluents in Resource-Limited Regions. Appl Environ Microbiol 86:e00616-20.
https://doi.org/10.1128/AEM.00616-20/</ref>

====Diagnostics====
In 2011, the FDA cleared the first bacteriophage-based product for in vitro diagnostic use.<ref>{{cite web | url = http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K102342 | title = FDA 510(k) Premarket Notification | publisher = U.S. Food and Drug Administration }}</ref> The KeyPath MRSA/MSSA Blood Culture Test uses a cocktail of bacteriophage to detect ''[[Staphylococcus aureus]]'' in positive blood cultures and determine [[methicillin]] resistance or susceptibility. The test returns results in about five hours, compared to two to three days for standard microbial identification and susceptibility test methods. It was the first accelerated antibiotic-susceptibility test approved by the FDA.<ref>{{cite journal | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254512.htm | title = FDA clears first test to quickly diagnose and distinguish MRSA and MSSA | publisher = U.S. Food and Drug Administration | date = 6 May 2011 | doi = 10.1128/aem.00616-20 | pmid = 32591380 | archive-url = https://web.archive.org/web/20150217175558/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254512.htm | archive-date = 17 February 2015 | journal = Applied and Environmental Microbiology | volume = 86 | issue = 17 | pmc = 7440787 | vauthors = Chacón L, Barrantes K, Santamaría-Ulloa C, Solano M, Reyes L, Taylor L, Valiente C, Symonds EM, Achí R | hdl = 10669/82145 | access-date = 17 February 2015 | url-status = bot: unknown }}</ref>

====Counteracting bioweapons and toxins====
Government agencies in the West have for several years been looking to [[Georgia (country)|Georgia]] and the former [[Soviet Union]] for help with exploiting phages for counteracting bioweapons and toxins, such as [[anthrax]] and [[botulism]].<ref>{{cite web | vauthors = Vaisman D | date = 25 May 2007 | url = https://www.nytimes.com/2007/05/25/world/americas/25iht-institute.4.5869943.html | title = Studying anthrax in a Soviet-era lab – with Western funding | work = The New York Times }}</ref> Developments are continuing among research groups in the U.S. Other uses include spray application in horticulture for protecting plants and vegetable produce from decay and the spread of bacterial disease. Other applications for bacteriophages are as biocides for environmental surfaces, e.g., in hospitals, and as preventative treatments for catheters and medical devices before use in clinical settings. The technology for phages to be applied to dry surfaces, e.g., uniforms, curtains, or even sutures for surgery now exists. Clinical trials reported in ''Clinical Otolaryngology''<ref name="Wright2009"/> show success in veterinary treatment of pet dogs with [[otitis]].

====Bacterium sensing and identification====
The [[sensing of phage-triggered ion cascades]] (SEPTIC) bacterium sensing and identification method uses the ion emission and its dynamics during phage infection and offers high specificity and speed for detection.<ref name="jbpc">{{cite journal |url=http://www.ece.tamu.edu/%7Enoise/research_files/King_et_al_JBPC.pdf | vauthors = Dobozi-King M, Seo S, Kim JU, Young R, Cheng M, Kish LB |title=Rapid detection and identification of bacteria: SEnsing of Phage-Triggered Ion Cascade (SEPTIC) |journal=Journal of Biological Physics and Chemistry |volume=5 |year=2005 |pages=3–7 |doi=10.4024/1050501.jbpc.05.01 |access-date=19 December 2016 |archive-date=26 September 2018 |archive-url=https://web.archive.org/web/20180926123955/http://www.ece.tamu.edu/%7Enoise/research_files/King_et_al_JBPC.pdf }}</ref>

====Phage display====
[[Phage display]] is a different use of phages involving a library of phages with a variable peptide linked to a surface protein. Each phage genome encodes the variant of the protein displayed on its surface (hence the name), providing a link between the peptide variant and its encoding gene. Variant phages from the library may be selected through their binding affinity to an immobilized molecule (e.g., botulism toxin) to neutralize it. The bound, selected phages can be multiplied by reinfecting a susceptible bacterial strain, thus allowing them to retrieve the peptides encoded in them for further study.<ref>{{cite journal | vauthors = Smith GP, Petrenko VA | title = Phage Display | journal = Chemical Reviews | volume = 97 | issue = 2 | pages = 391–410 | date = April 1997 | pmid = 11848876 | doi = 10.1021/cr960065d }}</ref>

====Antimicrobial drug discovery====
Phage proteins often have antimicrobial activity and may serve as leads for [[peptidomimetic]]s, i.e. drugs that mimic peptides.<ref>{{cite journal | vauthors = Liu J, Dehbi M, Moeck G, Arhin F, Bauda P, Bergeron D, Callejo M, Ferretti V, Ha N, Kwan T, McCarty J, Srikumar R, Williams D, Wu JJ, Gros P, Pelletier J, DuBow M | title = Antimicrobial drug discovery through bacteriophage genomics | journal = Nature Biotechnology | volume = 22 | issue = 2 | pages = 185–191 | date = February 2004 | pmid = 14716317 | doi = 10.1038/nbt932 | s2cid = 9905115 }}</ref> [[Phage-ligand technology]] makes use of phage proteins for various applications, such as binding of bacteria and bacterial components (e.g. [[endotoxin]]) and lysis of bacteria.<ref>{{cite web | url = http://www.hyglos.de/en/technology/technological-background.html | title = Technological background Phage-ligand technology | work = bioMérieux }}</ref>

====Basic research====
Bacteriophages are important [[model organisms]] for studying principles of [[evolution]] and [[ecology]].<ref>{{cite journal | vauthors = Keen EC | title = Tradeoffs in bacteriophage life histories | journal = Bacteriophage | volume = 4 | issue = 1 | pages = e28365 | date = January 2014 | pmid = 24616839 | pmc = 3942329 | doi = 10.4161/bact.28365 }}</ref>