Editing Antibiotic (section)

==History==
{{For timeline|Timeline of antibiotics}}

Before the early 20th century, treatments for infections were based primarily on [[folk medicine|medicinal folklore]]. Mixtures with antimicrobial properties that were used in treatments of infections were described over 2,000 years ago.<ref name="Considerations for Determining if a Natural Product Is an Effective Wound-Healing Agent"/> Many ancient cultures, including the [[Ancient Egyptian medicine|ancient Egyptians]] and [[Ancient Greek medicine|ancient Greeks]], used specially selected [[Mold (fungus)|mold]] and plant materials to treat [[infection]]s.<ref name="Early history of wound treatment"/><ref name="Moulds in ancient and more recent medicine"/> [[Nubian people|Nubian]] mummies studied in the 1990s were found to contain significant levels of [[tetracycline]]. The beer brewed at that time was conjectured to have been the source.<ref>{{cite journal | vauthors = Armelagos, George | date = 2000 | title = Take Two Beers and Call Me in 1,600 Years: Use of Tetracycline by Nubians and Ancient Egyptians | journal = Natural History | issue = 5; May | pages = 50–53 | url = https://ay14-15.moodle.wisc.edu/prod/pluginfile.php/59948/mod_resource/content/0/Take_two_Beers.pdf | access-date = 13 March 2017 }}{{Dead link|date=October 2022 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

The use of antibiotics in modern medicine began with the discovery of synthetic antibiotics derived from dyes.<ref name="CALDERIN2007"/><ref name="Limbird2004"/><ref name="Bosch2008"/><ref name="ReferenceB">{{cite journal | vauthors = Williams KJ | title = The introduction of 'chemotherapy' using arsphenamine - the first magic bullet | journal = Journal of the Royal Society of Medicine | volume = 102 | issue = 8 | pages = 343–348 | date = August 2009 | pmid = 19679737 | pmc = 2726818 | doi = 10.1258/jrsm.2009.09k036 }}</ref><ref name="goodman">{{cite book | vauthors = Goodman LS, Gilman A |author-link1=Louis S. Goodman |author-link2=Alfred Gilman, Sr. |title=The Pharmacological Basis of Therapeutics |publisher=Macmillan |location=New York |year=1941|title-link=The Pharmacological Basis of Therapeutics }}</ref> Various [[Essential oil]]s have been shown to have anti-microbial properties.<ref>{{cite journal | vauthors = Chouhan S, Sharma K, Guleria S | title = Antimicrobial Activity of Some Essential Oils-Present Status and Future Perspectives | journal = Medicines | volume = 4 | issue = 3 | pages = 58 | date = August 2017 | pmid = 28930272 | pmc = 5622393 | doi = 10.3390/medicines4030058 | doi-access = free | title-link = doi }}</ref> Along with this, the plants from which these oils have been derived can be used as niche anti-microbial agents.<ref>{{cite journal | vauthors = Cowan MM | title = Plant products as antimicrobial agents | journal = Clinical Microbiology Reviews | volume = 12 | issue = 4 | pages = 564–582 | date = October 1999 | pmid = 10515903 | pmc = 88925 | doi = 10.1128/CMR.12.4.564 }}</ref>

===Synthetic antibiotics derived from dyes===
[[File:Salvarsan-montage.png|thumb|right|upright=0.9|Arsphenamine, also known as salvarsan, discovered in 1907 by Paul Ehrlich]]
Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with [[Paul Ehrlich]] in the late 1880s.<ref name="CALDERIN2007"/> Ehrlich noted certain dyes would colour human, animal, or bacterial cells, whereas others did not. He then proposed the idea that it might be possible to create chemicals that would act as a selective drug that would bind to and kill bacteria without harming the human host. After screening hundreds of dyes against various organisms, in 1907, he discovered a medicinally useful drug, the first synthetic antibacterial [[Organoarsenic chemistry|organoarsenic compound]] [[salvarsan]],<ref name="CALDERIN2007"/><ref name="Limbird2004"/><ref name="Bosch2008"/> now called arsphenamine.
[[File:Paul Ehrlich and Sahachiro Hata.jpg|thumb|left|[[Paul Ehrlich]] and [[Sahachiro Hata]] ]]
This heralded the era of antibacterial treatment that was begun with the discovery of a series of arsenic-derived synthetic antibiotics by both [[Alfred Bertheim]] and Ehrlich in 1907.<ref name="ReferenceB"/><ref name="goodman"/> Ehrlich and Bertheim had experimented with various chemicals derived from dyes to treat [[trypanosomiasis]] in mice and [[spirochaeta]] infection in rabbits. While their early compounds were too toxic, Ehrlich and [[Sahachiro Hata]], a Japanese bacteriologist working with Ehrlich in the quest for a drug to treat [[syphilis]], achieved success with the 606th compound in their series of experiments. In 1910, Ehrlich and Hata announced their discovery, which they called drug "606", at the Congress for Internal Medicine at [[Wiesbaden]].<ref name="jmvh.org">{{cite journal|vauthors=Frith J|title=Arsenic – the "Poison of Kings" and the "Saviour of Syphilis"|journal=Journal of Military and Veterans' Health|volume=21|issue=4|url=http://jmvh.org/article/arsenic-the-poison-of-kings-and-the-saviour-of-syphilis/|access-date=31 January 2017|archive-date=26 February 2017|archive-url=https://web.archive.org/web/20170226102745/http://jmvh.org/article/arsenic-the-poison-of-kings-and-the-saviour-of-syphilis/|url-status=live}}</ref> The [[Hoechst AG|Hoechst]] company began to market the compound toward the end of 1910 under the name Salvarsan, now known as [[arsphenamine]].<ref name="jmvh.org"/> The drug was used to treat syphilis in the first half of the 20th century. In 1908, Ehrlich received the [[Nobel Prize in Physiology or Medicine]] for his contributions to [[immunology]].<ref name=nobel>{{cite web|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1908/ehrlich-bio.html|title=The Nobel Prize in Physiology or Medicine 1908|website=NobelPrize.org|access-date=13 June 2017|archive-date=14 August 2018|archive-url=https://web.archive.org/web/20180814214526/https://www.nobelprize.org/nobel_prizes/medicine/laureates/1908/ehrlich-bio.html|url-status=live}}</ref> Hata was nominated for the [[Nobel Prize in Chemistry]] in 1911 and for the Nobel Prize in Physiology or Medicine in 1912 and 1913.<ref>{{cite web|url=https://www.nobelprize.org/nomination/archive/show_people.php?id=3941|title=Nomination Archive|date=April 2020|website=NobelPrize.org|access-date=13 June 2017|archive-date=26 July 2020|archive-url=https://web.archive.org/web/20200726053416/https://www.nobelprize.org/nomination/archive/show_people.php?id=3941|url-status=live}}</ref>

The first [[sulfonamide (medicine)|sulfonamide]] and the first [[wikt:systemic|systemically]] active antibacterial drug, [[Prontosil]], was developed by a research team led by [[Gerhard Domagk]] in 1932 or 1933 at the [[Bayer]] Laboratories of the [[IG Farben]] conglomerate in Germany,<ref name="goodman"/><ref name="ReferenceA"/><ref name="Bosch2008"/> for which Domagk received the 1939 Nobel Prize in Physiology or Medicine.<ref>{{cite web |url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1939/press.html |title=Physiology or Medicine 1939 – Presentation Speech |publisher=Nobel Foundation |access-date=14 January 2015 |archive-date=14 January 2015 |archive-url=https://web.archive.org/web/20150114032532/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1939/press.html |url-status=live }}</ref> Sulfanilamide, the active drug of Prontosil, was not patentable as it had already been in use in the dye industry for some years.<ref name="ReferenceA"/> Prontosil had a relatively broad effect against [[Gram-positive]] [[coccus|cocci]], but not against [[Enterobacteriaceae|enterobacteria]]. Research was stimulated apace by its success. The discovery and development of this sulfonamide [[drug]] opened the era of antibacterials.<ref>{{cite journal | vauthors = Wright PM, Seiple IB, Myers AG | title = The evolving role of chemical synthesis in antibacterial drug discovery | journal = Angewandte Chemie | volume = 53 | issue = 34 | pages = 8840–69 | date = August 2014 | pmid = 24990531 | pmc = 4536949 | doi = 10.1002/anie.201310843 }}</ref><ref>{{cite journal | vauthors = Aminov RI | title = A brief history of the antibiotic era: lessons learned and challenges for the future | journal = Frontiers in Microbiology | volume = 1 | pages = 134 | date = 1 January 2010 | pmid = 21687759 | pmc = 3109405 | doi = 10.3389/fmicb.2010.00134 | doi-access = free | title-link = doi }}</ref>

===Penicillin and other natural antibiotics===
{{See also|History of penicillin}}
[[File:Penicillin core.svg|thumb|upright=0.75|class=skin-invert-image|[[Penicillin]], discovered by [[Alexander Fleming]] in 1928]]
Observations about the growth of some microorganisms inhibiting the growth of other microorganisms have been reported since the late 19th century. These observations of antibiosis between microorganisms led to the discovery of natural antibacterials. [[Louis Pasteur]] observed, "if we could intervene in the antagonism observed between some bacteria, it would offer perhaps the greatest hopes for therapeutics".<ref name="Kingston2008"/>

In 1874, physician Sir [[William Roberts (physician)|William Roberts]] noted that cultures of the mould ''[[Penicillium glaucum]]'' that is used in the making of some types of [[blue cheese]] did not display bacterial contamination.<ref>{{cite journal | vauthors = Foster W, Raoult A | title = Early descriptions of antibiosis | journal = The Journal of the Royal College of General Practitioners | volume = 24 | issue = 149 | pages = 889–94 | date = December 1974 | pmid = 4618289 | pmc = 2157443 | quote = the first scientific observations of the antagonistic actions of various micro-organisms were made ... by William Roberts of Manchester (1874) and John Tyndall of London (1876). }}</ref>

In 1895 [[Vincenzo Tiberio]], Italian physician, published a paper on the antibacterial power of some extracts of mold.<ref>{{Cite journal |vauthors=Bucci R, Gallì P |date=11 May 2012 |title=Public Health History Corner Vincenzo Tiberio: a misunderstood researcher |url=http://ijphjournal.it/article/view/5688 |journal=Italian Journal of Public Health |volume=8 |issue=4 |access-date=30 September 2017 |archive-date=20 September 2018 |archive-url=https://web.archive.org/web/20180920160850/https://ijphjournal.it/article/view/5688 |url-status=dead }}</ref>

In 1897, doctoral student [[Ernest Duchesne]] submitted a dissertation, "{{lang|fr|Contribution à l'étude de la concurrence vitale chez les micro-organismes: antagonisme entre les moisissures et les microbes}}" (Contribution to the study of vital competition in micro-organisms: antagonism between moulds and microbes),<ref>{{cite book | vauthors = Duchesne E | translator = Witty M |title= Duchesne's Antagonism between molds and bacteria, an English Colloquial Translation| isbn= 978-1-5498-1696-3|date= 23 September 2017 | publisher = Independently Published }}</ref> the first known scholarly work to consider the therapeutic capabilities of moulds resulting from their anti-microbial activity. In his thesis, Duchesne proposed that bacteria and moulds engage in a perpetual battle for survival. Duchesne observed that ''[[Escherichia coli|E. coli]]'' was eliminated by ''Penicillium glaucum'' when they were both grown in the same culture. He also observed that when he [[inoculation|inoculated]] laboratory animals with lethal doses of [[typhoid]] bacilli together with ''Penicillium glaucum'', the animals did not contract typhoid. Duchesne's army service after getting his degree prevented him from doing any further research.<ref name="Academic Press">{{cite book|vauthors=Straand J, Gradmann C, Simonsen GS, Lindbæk M|title=International Encyclopedia of Public Health: Antibiotic Development and Resistance|date=2008|publisher=Academic Press|pages=200|url=http://www.sciencedirect.com/topics/page/Arsphenamine|access-date=31 January 2017|archive-date=4 October 2016|archive-url=https://web.archive.org/web/20161004031024/http://www.sciencedirect.com/topics/page/Arsphenamine|url-status=live}}</ref> Duchesne died of [[tuberculosis]], a disease now treated by antibiotics.<ref name="Academic Press"/>

In 1928, Sir [[Alexander Fleming]] postulated the existence of [[penicillin]], a molecule produced by certain moulds that kills or stops the growth of certain kinds of bacteria. Fleming was working on a culture of [[pathogen|disease-causing]] bacteria when he noticed the [[spore]]s of a green mold, ''[[Penicillium rubens]]'',<ref name="pmid32973216">{{cite journal |vauthors=Pathak A, Nowell RW, Wilson CG, Ryan MJ, Barraclough TG|date=September 2020 |title=Comparative genomics of Alexander Fleming's original ''Penicillium'' isolate (IMI 15378) reveals sequence divergence of penicillin synthesis genes|journal=Scientific Reports|volume=10 |issue=1 |pages=Article 15705 |doi=10.1038/s41598-020-72584-5|pmid=32973216|pmc=7515868|bibcode=2020NatSR..1015705P }}</ref> in one of his [[agar plate|culture plates]]. He observed that the presence of the mould killed or prevented the growth of the bacteria.<ref>{{cite journal | vauthors = Tan SY, Tatsumura Y | title = Alexander Fleming (1881-1955): Discoverer of penicillin | journal = Singapore Medical Journal | volume = 56 | issue = 7 | pages = 366–7 | date = July 2015 | pmid = 26243971 | pmc = 4520913 | doi = 10.11622/smedj.2015105 }}</ref> Fleming postulated that the mould must secrete an antibacterial substance, which he named penicillin in 1928. Fleming believed that its antibacterial properties could be exploited for chemotherapy. He initially characterised some of its biological properties, and attempted to use a crude preparation to treat some infections, but he was unable to pursue its further development without the aid of trained chemists.<ref name="Fleming1929"/><ref name="Sykes2001"/>

[[Ernst Chain]], [[Howard Florey]] and [[Edward Abraham]] succeeded in purifying the first penicillin, [[penicillin G]], in 1942, but it did not become widely available outside the Allied military before 1945. Later, [[Norman Heatley]] developed the back extraction technique for efficiently purifying penicillin in bulk. The chemical structure of penicillin was first proposed by Abraham in 1942<ref>{{Cite journal|vauthors=Jones DS, Jones JH|date=1 December 2014|title=Sir Edward Penley Abraham CBE. 10 June 1913 – 9 May 1999|url=http://rsbm.royalsocietypublishing.org/content/60/5.1|journal=Biographical Memoirs of Fellows of the Royal Society|language=en|volume=60|pages=5–22|doi=10.1098/rsbm.2014.0002|issn=0080-4606| doi-access = free | title-link = doi |access-date=10 May 2017|archive-date=26 November 2023|archive-url=https://web.archive.org/web/20231126055623/http://rsbm.royalsocietypublishing.org/content/60/5.1|url-status=live}}</ref> and then later confirmed by [[Dorothy Crowfoot Hodgkin]] in 1945. Purified penicillin displayed potent antibacterial activity against a wide range of bacteria and had low toxicity in humans. Furthermore, its activity was not inhibited by biological constituents such as pus, unlike the synthetic [[sulfonamides]]. (see below) The development of penicillin led to renewed interest in the search for antibiotic compounds with similar efficacy and safety.<ref name="Use of Micro-organisms for therapeutic purposes"/> For their successful development of penicillin, which Fleming had accidentally discovered but could not develop himself, as a therapeutic drug, Chain and Florey shared the 1945 [[Nobel Prize in Medicine]] with Fleming.<ref>{{cite web |url=https://www.nobelprize.org/prizes/medicine/1945/summary/ |access-date=13 January 2018 |title=The Nobel Prize in Physiology or Medicine 1945 |publisher=The Nobel Prize Organization |archive-date=23 May 2020 |archive-url=https://web.archive.org/web/20200523072137/https://www.nobelprize.org/prizes/medicine/1945/summary/ |url-status=live }}</ref>

Florey credited [[René Dubos]] with pioneering the approach of deliberately and systematically searching for antibacterial compounds, which had led to the discovery of gramicidin and had revived Florey's research in penicillin.<ref name=Epps2006/> In 1939, coinciding with the start of [[World War II]], Dubos had reported the discovery of the first naturally derived antibiotic, [[tyrothricin]], a compound of 20% [[gramicidin]] and 80% [[tyrocidine]], from ''Bacillus brevis''. It was one of the first commercially manufactured antibiotics and was very effective in treating wounds and ulcers during World War II.<ref name="Epps2006"/> Gramicidin, however, could not be used systemically because of toxicity. Tyrocidine also proved too toxic for systemic usage. Research results obtained during that period were not shared between the [[Axis powers|Axis]] and the [[Allied powers of World War II|Allied powers]] during World War II and limited access during the [[Cold War]].<ref>{{cite journal | vauthors = Capocci M | title = Cold drugs. Circulation, production and intelligence of antibiotics in post-WWII years | journal = Medicina Nei Secoli | volume = 26 | issue = 2 | pages = 401–21 | date = 1 January 2014 | pmid = 26054208 }}</ref>

===Late 20th century===
During the mid-20th century, the number of new antibiotic substances introduced for medical use increased significantly. From 1935 to 1968, 12 new classes were launched. However, after this, the number of new classes dropped markedly, with only two new classes introduced between 1969 and 2003.<ref>{{cite journal | vauthors = Conly J, Johnston B | title = Where are all the new antibiotics? The new antibiotic paradox | journal = The Canadian Journal of Infectious Diseases & Medical Microbiology | volume = 16 | issue = 3 | pages = 159–60 | date = May 2005 | pmid = 18159536 | pmc = 2095020 | doi = 10.1155/2005/892058 | doi-access = free | title-link = doi }}</ref>