Editing Penicillin (section)

== History ==
{{Main|History of penicillin}}

=== Discovery ===
{{main|Discovery of penicillin}}
[[File:Sample of penicillin mould presented by Alexander Fleming to Douglas Macleod, 1935 (9672239344).jpg|thumb|Sample of ''[[penicillium]]'' mould presented by [[Alexander Fleming]] to Douglas Macleod, 1935]]

Starting in the late 19th century there had been reports of the antibacterial properties of ''Penicillium'' mould, but scientists were unable to discern what process was causing the effect.<ref>{{cite book | vauthors = Dougherty TJ, Pucci MJ | title = Antibiotic Discovery and Development | publisher = Springer Science & Business Media | date = 2011 | pages = 79–80 }}</ref> Scottish physician [[Alexander Fleming]] at [[St Mary's Hospital, London|St. Mary's Hospital]] in London (now part of [[Imperial College]]) was the first to show that ''[[Penicillium rubens]]'' had antibacterial properties.<ref>{{cite book | vauthors = Landau R, Achilladelis B, Scriabine A | title = Pharmaceutical Innovation: Revolutionizing Human Health | publisher = Chemical Heritage Foundation | date = 1999 | page = 162 }}</ref> On 3 September 1928 he observed by chance that fungal contamination of a bacterial culture (''[[Staphylococcus aureus]]'') appeared to kill the bacteria. He confirmed this observation with a new experiment on 28 September 1928.<ref>{{cite book | vauthors = Haven KF |title=Marvels of Science: 50 Fascinating 5-Minute Reads |publisher=Libraries Unlimited |location=Littleton, CO |year=1994 |page=182 |isbn=978-1-56308-159-0 }}</ref><ref>{{cite journal | vauthors = Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D | title = 10 x '20 Progress – development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America | journal = Clinical Infectious Diseases | volume = 56 | issue = 12 | pages = 1685–94 | date = June 2013 | pmc = 5403050 | doi = 10.3201/eid2305.161556 | pmid = 23599308 }}</ref> He published his experiment in 1929, and called the antibacterial substance (the fungal extract) penicillin.<ref name="Fleming1929">{{cite journal |title=On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to their Use in the Isolation of B. influenzæ | vauthors = Fleming A | journal = British Journal of Experimental Pathology |year=1929 |volume=10|issue=3|pages=226–36|pmc=2048009}}
Reprinted as {{cite journal | vauthors = Fleming A | title = Classics in infectious diseases: on the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae by Alexander Fleming, Reprinted from the British Journal of Experimental Pathology 10:226–36, 1929 | journal = Reviews of Infectious Diseases | volume = 2 | issue = 1 | pages = 129–39 | year = 1980 | pmid = 6994200 | pmc = 2041430 | doi = 10.1093/clinids/2.1.129 }}</ref>

C. J. La Touche identified the fungus as ''Penicillium rubrum'' (later reclassified by [[Charles Thom]] as ''P. notatum'' and ''P. chrysogenum'', but later corrected as ''[[Penicillium rubens|P. rubens]]'').<ref>{{cite journal | vauthors = Houbraken J, Frisvad JC, Samson RA | title = Fleming's penicillin producing strain is not Penicillium chrysogenum but P. rubens | journal = IMA Fungus | volume = 2 | issue = 1 | pages = 87–95 | date = June 2011 | pmid = 22679592 | pmc = 3317369 | doi = 10.5598/imafungus.2011.02.01.12 }}</ref> Fleming expressed initial optimism that penicillin would be a useful antiseptic, because of its high potency and minimal toxicity in comparison to other antiseptics of the day, and noted its laboratory value in the isolation of ''Bacillus influenzae'' (now called ''[[Haemophilus influenzae]]'').<ref name="Lax2004">{{cite book| vauthors = Lax E  |url= https://archive.org/details/moldindrfloreysc00eric |title=The Mold in Dr. Florey's Coat: The Story of the Penicillin Miracle |publisher=Holt Paperbacks |year=2004 |isbn=978-0-8050-7778-0 }}</ref><ref name=Krylov1991>{{cite journal | vauthors = Krylov AK | title = [Gastroenterologic aspects of the clinical picture of internal diseases] | journal = Terapevticheskii Arkhiv | volume = 63 | issue = 2 | pages = 139–41 | year = 1991 | pmid = 2048009 }}</ref>
<!--Reprinted in {{cite journal | vauthors = Fleming A | title = On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. 1929 | journal = Bulletin of the World Health Organization | volume = 79 | issue = 8 | pages = 780–90 | year = 2001 | pmid = 11545337 | pmc = 2566493 }}   This made absolutely no sense at all. The Russian paper is from 1991, and could not have been reprinted in Fleming's original 1929 paper. The ''Bulletin'' link is to an image PDF of of Fleming's paper. There is another link above to a reprint of Fleming's paper in ''Reviews of Infectious Diseases''-->

Fleming did not convince anyone that his discovery was important.<ref name=Lax2004 /> This was largely because penicillin was so difficult to isolate that its development as a drug seemed impossible. It is speculated that had Fleming been more successful at making other scientists interested in his work, penicillin would possibly have been developed years earlier.<ref name=Lax2004 />

The importance of his work has been recognized by the placement of an [[International Historic Chemical Landmark]] at the Alexander Fleming Laboratory Museum in London on 19 November 1999.<ref name="Landmark">{{cite web |title = Discovery and Development of Penicillin |url = https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html |publisher = American Chemical Society |work = International Historic Chemical Landmarks |access-date = August 21, 2018 |archive-date = June 28, 2019 |archive-url = https://web.archive.org/web/20190628035235/https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html |url-status = live }}</ref>

=== Development and medical application ===
[[File:Howard Walter Florey 1945.jpg|thumb|upright=0.8|[[Howard Florey]] (pictured), Alexander Fleming and [[Ernst Chain]] shared a [[Nobel Prize in Physiology or Medicine]] in 1945 for their work on penicillin.]]
In 1930, Cecil George Paine, a [[pathologist]] at the [[Sheffield Royal Infirmary|Royal Infirmary]] in [[Sheffield]], successfully treated [[Neonatal conjunctivitis|ophthalmia neonatorum]], a gonococcal infection in infants, with penicillin (fungal extract) on November 25, 1930.<ref name="Wainwright, M & Swan, HT 1986 42–56">{{cite journal | vauthors = Wainwright M, Swan HT | title = C.G. Paine and the earliest surviving clinical records of penicillin therapy | journal = Medical History | volume = 30 | issue = 1 | pages = 42–56 | date = January 1986 | pmid = 3511336 | pmc = 1139580 | doi = 10.1017/S0025727300045026 }}</ref><ref>{{cite journal | vauthors = Howie J | title = Penicillin: 1929-40 | journal = British Medical Journal | volume = 293 | issue = 6540 | pages = 158–59 | date = July 1986 | pmid = 3089435 | pmc = 1340901 | doi = 10.1136/bmj.293.6540.158 }}</ref><ref>{{cite journal | vauthors = Wainwright M | title = The history of the therapeutic use of crude penicillin | journal = Medical History | volume = 31 | issue = 1 | pages = 41–50 | date = January 1987 | pmid = 3543562 | pmc = 1139683 | doi = 10.1017/s0025727300046305 }}</ref>

In 1940, Australian scientist [[Howard Walter Florey|Howard Florey]] (later Baron Florey) and a team of researchers ([[Ernst Boris Chain|Ernst Chain]], [[Edward Abraham]], [[Arthur Duncan Gardner]], [[Norman Heatley]], [[Margaret Jennings (scientist)|Margaret Jennings]], [[Jean Orr-Ewing]] and Arthur Gordon Sanders) at the Sir William Dunn School of Pathology, [[University of Oxford]] made progress in making concentrated penicillin from fungal culture broth that showed both ''in vitro'' and ''[[in vivo]]'' bactericidal action.<ref name=":0" /><ref>{{Cite web|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/chain-lecture.html|title=Ernst B. Chain – Nobel Lecture: The Chemical Structure of the Penicillins|website=www.nobelprize.org|access-date=2017-05-10|archive-date=2017-04-30|archive-url=https://web.archive.org/web/20170430172918/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/chain-lecture.html|url-status=live}}</ref> In 1941, they treated a policeman, [[Albert Alexander (police officer)|Albert Alexander]], with a severe face infection; his condition improved, but then supplies of penicillin ran out and he died. Subsequently, several other patients were treated successfully.<ref name="SW" /> In December 1942, survivors of the [[Cocoanut Grove fire]] in Boston were the first burn patients to be successfully treated with penicillin.<ref>{{cite book | vauthors = Levy SB | title = The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Powers | publisher = Da Capo Press | year = 2002 | pages = 5–7 | isbn = 978-0-7382-0440-6 }}</ref>

The first successful use of pure penicillin was in 1942 when Fleming cured Harry Lambert of an infection of the nervous system (streptococcal [[meningitis]]) which would otherwise have been fatal. By that time the Oxford team could produce only a small amount. Florey willingly gave the only available sample to Fleming. Lambert showed improvement from the very next day of the treatment, and was completely cured within a week.<ref name=":42">{{cite journal | vauthors = Bennett JW, Chung KT | title = Alexander Fleming and the discovery of penicillin | journal = Advances in Applied Microbiology | volume = 49 | pages = 163–84 | date = 2001 | pmid = 11757350 | doi = 10.1016/s0065-2164(01)49013-7 | publisher = Elsevier | isbn = 978-0-12-002649-4 }}</ref><ref>{{Cite journal| vauthors = Cairns H, Lewin WS, Duthie ES, Smith H |date=1944|title=Pneumococcal Meningitis Treated with Penicillin |journal=The Lancet|language=en|volume=243|issue=6299|pages=655–59|doi=10.1016/S0140-6736(00)77085-1}}</ref> Fleming published his clinical trial in ''[[The Lancet]]'' in 1943.<ref name="Fleming 1943 434–438"/> Following the medical breakthrough, the British [[War Cabinet]] set up the Penicillin Committee on 5 April 1943 that led to projects for [[mass production]].<ref>{{Cite journal| vauthors = Mathews JA |date=2008|title=The Birth of the Biotechnology Era: Penicillin in Australia, 1943–80 |journal=Prometheus|volume=26|issue=4|pages=317–33|doi=10.1080/08109020802459306|s2cid=143123783}}</ref><ref>{{Cite book|vauthors=Baldry P|url=https://books.google.com/books?id=rvs8AAAAIAAJ|title=The Battle Against Bacteria: A Fresh Look|date=1976|publisher=CUP Archive|isbn=978-0-521-21268-7|pages=115|language=en|access-date=2020-12-31|archive-date=2021-05-05|archive-url=https://web.archive.org/web/20210505180529/https://books.google.com/books?id=rvs8AAAAIAAJ|url-status=live}}</ref>

=== Mass production ===
[[File:Penicillin Past, Present and Future- the Development and Production of Penicillin, England, 1943 D16965.jpg|thumb|A lab technician spraying penicillin mould into flasks of corn steep liquor, England, 1943]]
As the medical application was established, the Oxford team found that it was impossible to produce usable amounts in their laboratory.<ref name=SW /> Failing to persuade the British government, Florey and Heatley travelled to the US in June 1941 with their mould samples in order to interest the US government for large-scale production.<ref name=":10">{{cite journal |vauthors=Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D |date=June 2013 |title=10 x '20 Progress – development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America |journal=Clinical Infectious Diseases |volume=56 |issue=12 |pages=1685–1694 |doi=10.1093/cid/cit152 |pmc=3707426 |pmid=23599308}}</ref><ref name=":2">{{Cite journal | vauthors = Braun A |date=December 2024 |title=A Most Miraculous Mold |journal=Smithsonian |volume=55 |issue=6 |page=32}}</ref> They approached the [[USDA]] Northern Regional Research Laboratory (NRRL, now the [[National Center for Agricultural Utilization Research]]) at Peoria, Illinois, where facilities for large-scale fermentations were established.<ref name=":12">{{Cite web|vauthors=Carroll A|date=2014-06-02|title=Here is Where: Penicillin Comes to Peoria|url=https://www.historynet.com/here-is-where-penicillin-comes-to-peoria.htm|access-date=2021-01-04|website=HistoryNet|language=en-US|archive-date=2021-01-07|archive-url=https://web.archive.org/web/20210107164913/https://www.historynet.com/here-is-where-penicillin-comes-to-peoria.htm|url-status=live}}</ref><ref name=":2" /> Mass culture of the mould and search for better moulds immediately followed.<ref name=":10" />

On March 14, 1942, the first patient was treated for streptococcal sepsis with US-made penicillin produced by [[Merck & Co.]]<ref name="pmid18626052">{{cite journal | vauthors = Grossman CM | title = The first use of penicillin in the United States | journal = Annals of Internal Medicine | volume = 149 | issue = 2 | pages = 135–36 | date = July 2008 | pmid = 18626052 | doi = 10.7326/0003-4819-149-2-200807150-00009 | s2cid = 40197907 }}</ref> Half of the total supply produced at the time was used on that one patient, Anne Miller.<ref>{{cite magazine|url=https://time.com/4250235/penicillin-1942-history/|title=Penicillin history: what happened to first American patient|magazine=[[Time (magazine)|Time]]|date=14 March 2016|vauthors=Rothman L|access-date=12 March 2019|archive-date=17 March 2019|archive-url=https://web.archive.org/web/20190317151512/http://time.com/4250235/penicillin-1942-history/|url-status=live}}</ref> By June 1942, just enough US penicillin was available to treat ten patients.<ref>{{cite web |vauthors=Mailer JS, Mason B |url=http://www.lib.niu.edu/2001/iht810139.html |title=Penicillin : Medicine's Wartime Wonder Drug and Its Production at Peoria, Illinois |publisher=lib.niu.edu |access-date=February 11, 2008 |archive-date=October 7, 2018 |archive-url=https://web.archive.org/web/20181007082158/http://www.lib.niu.edu/2001/iht810139.html |url-status=live }}</ref> In July 1943, the [[War Production Board]] drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe.<ref name="JParas" /> The results of fermentation research on [[corn steep liquor]] at the NRRL allowed the United States to produce 2.3&nbsp;million doses in time for the [[invasion of Normandy]] in the spring of 1944. After a worldwide search in 1943, a mouldy [[cantaloupe]] in a [[Peoria, Illinois]] market was found to contain the best strain of mould for production using the corn steep liquor process.<ref>{{Cite web |title=The History of Penicillin and Antibiotics |url=https://www.thoughtco.com/history-of-penicillin-1992304 |access-date=2024-06-09 |website=ThoughtCo |language=en |archive-date=2023-04-08 |archive-url=https://web.archive.org/web/20230408215937/https://www.thoughtco.com/history-of-penicillin-1992304 |url-status=live }}</ref> Six times as much penicillin could be produced compared to using Fleming's mold.<ref name=":2" /> [[Pfizer]] scientist [[Jasper H. Kane]] suggested using a deep-tank fermentation method for producing large quantities of pharmaceutical-grade penicillin.<ref name="Lehrer2006">{{cite book| vauthors = Lehrer S |title=Explorers of the Body: Dramatic Breakthroughs in Medicine from Ancient Times to Modern Science|date=2006|publisher=iUniverse|location=New York|isbn=978-0-595-40731-6|pages=329–30|edition=2nd}}</ref><ref name="Greenwood_2008" />{{rp|109}} Large-scale production resulted from the development of a deep-tank fermentation plant by [[chemical engineer]] [[Margaret Hutchinson Rousseau]].<ref name="Madhavan">{{cite book|vauthors=Madhavan G|title=Think Like an Engineer|date=Aug 20, 2015|publisher=Oneworld Publications|isbn=978-1-78074-637-1|pages=83–85, 91–93|url=https://books.google.com/books?id=GNAfCgAAQBAJ&pg=PT44|access-date=20 November 2016|archive-date=23 March 2017|archive-url=https://web.archive.org/web/20170323204621/https://books.google.com/books?id=GNAfCgAAQBAJ&pg=PT44|url-status=live}}</ref> As a direct result of the war and the War Production Board, by June 1945, over 646&nbsp;billion units per year were being produced.<ref name="JParas">{{cite book| vauthors = Parascandola J |author-link=John Parascandola |title=The History of antibiotics: a symposium| publisher=American Institute of the History of Pharmacy No. 5 |year=1980 |isbn=978-0-931292-08-8 }}</ref>

[[G. Raymond Rettew]] made a significant contribution to the American war effort by his techniques to produce commercial quantities of penicillin, wherein he combined his knowledge of mushroom spawn with the function of the Sharples Cream Separator.<ref>{{cite web|title=G. Raymond Rettew Historical Marker|url=http://explorepahistory.com/hmarker.php?markerId=1-A-2F2|website=ExplorePAhistory.com|access-date=June 27, 2019|archive-date=January 5, 2020|archive-url=https://web.archive.org/web/20200105212951/http://explorepahistory.com/hmarker.php?markerId=1-A-2F2|url-status=live}}</ref> By 1943, Rettew's lab was producing most of the world's penicillin. During [[World War II]], penicillin made a major difference in the number of deaths and amputations caused by infected wounds among [[Allies of World War II|Allied]] forces, saving an estimated 12–15% of lives.<ref>{{Cite journal|vauthors=Goyotte D|date=2017|title=The Surgical Legacy of World War II. Part II: The age of antibiotics|url=https://www.ast.org/ceonline/articles/402/files/assets/common/downloads/publication.pdf|journal=The Surgical Technologist|volume=109|pages=257–64|via=|access-date=2021-01-08|archive-date=2021-05-05|archive-url=https://web.archive.org/web/20210505180530/https://www.ast.org/ceonline/articles/402/files/assets/common/downloads/publication.pdf|url-status=live}}</ref> Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid [[clearance (medicine)|renal clearance]] of the drug, necessitating frequent dosing. Methods for mass production of penicillin were patented by [[Andrew Jackson Moyer]] in 1945.<ref>{{cite patent | country = US | number = 2442141 | inventor = Moyer AJ | assign1 = US Agriculture | title = Method for Production of Penicillin | gdate = 25 March 1948 }}</ref><ref>{{cite patent | country = US | number = 2443989 | inventor = Moyer AJ | assign1 = US Agriculture | title = Method for Production of Penicillin | gdate = 22 June 1948 }}</ref><ref>{{cite patent | country = US | number = 2476107 | inventor = Moyer AJ | assign1 = US Agriculture | title = Method for Production of Penicillin | gdate = 12 July 1949 }}</ref> Florey had not patented penicillin, having been advised by Sir [[Henry Hallett Dale|Henry Dale]] that doing so would be unethical.<ref name="SW">{{cite web | title = Making Penicillin Possible: Norman Heatley Remembers | access-date = 2007-02-13 | year = 2007 | work = ScienceWatch | publisher = [[Thomson Scientific]]| url=http://www.sciencewatch.com/interviews/norman_heatly.htm | archive-url= https://web.archive.org/web/20070221041204/http://www.sciencewatch.com/interviews/norman_heatly.htm| archive-date=February 21, 2007}}</ref>

Penicillin is actively excreted, and about 80% of a penicillin dose is cleared from the body within three to four hours of administration. Indeed, during the early penicillin era, the drug was so scarce and so highly valued that it became common to collect the urine from patients being treated, so that the penicillin in the urine could be isolated and reused.<ref name=Silverthorn2004>{{cite book | vauthors=Silverthorn DU | title=Human physiology: an integrated approach. | edition=3rd | location=Upper Saddle River (NJ) | publisher=Pearson Education | year=2004 | isbn=978-0-8053-5957-2 | url-access=registration | url=https://archive.org/details/humanphysiology00deeu }}</ref> This was not a satisfactory solution, so researchers looked for a way to slow penicillin excretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for excretion, such that the transporter would preferentially excrete the competing molecule and the penicillin would be retained. The [[uricosuric]] agent [[probenecid]] proved to be suitable. When probenecid and penicillin are administered together, probenecid competitively inhibits the excretion of penicillin, increasing penicillin's concentration and prolonging its activity. Eventually, the advent of mass-production techniques and semi-synthetic penicillins resolved the supply issues, so this use of probenecid declined.<ref name=Silverthorn2004 /> Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.<ref>{{cite journal | vauthors = Luque Paz D, Lakbar I, Tattevin P | title = A review of current treatment strategies for infective endocarditis | journal = Expert Review of Anti-Infective Therapy | volume = 19 | issue = 3 | pages = 297–307 | date = March 2021 | pmid = 32901532 | doi = 10.1080/14787210.2020.1822165 | s2cid = 221572394 }}</ref>

After World War II, Australia was the first country to make the drug available for civilian use. In the U.S., penicillin was made available to the general public on March 15, 1945.<ref name="DR">{{cite web | url = http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html | title = Discovery and development of penicillin | publisher = [[American Chemical Society]] | year = 1999 | access-date = 2015-01-04 | archive-date = 2015-01-03 | archive-url = https://web.archive.org/web/20150103210448/http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html | url-status = live }}</ref>

Fleming, Florey, and Chain shared the 1945 Nobel Prize in Physiology or Medicine for the development of penicillin.

<gallery widths="200px" heights="200px">
File:Penicillin Past, Present and Future- the Development and Production of Penicillin, England, 1943 D16959.jpg|A technician preparing penicillin in 1943
File:PenicillinPSAedit.jpg|Penicillin was being mass-produced in 1944.
File:Penicillin poster 5.40.tif|World War II poster extolling use of penicillin
File:Dorothy Hodgkin Nobel.jpg|[[Dorothy Hodgkin]] determined the chemical structure of penicillin.
</gallery>

=== Structure determination and total synthesis ===
[[File:Molecular model of Penicillin by Dorothy Hodgkin (9663803982).jpg|thumb|Dorothy Hodgkin's model of penicillin's structure]]
The [[chemical structure]] of penicillin was first proposed by [[Edward Abraham]] in 1942<ref name=":0">{{Cite journal|vauthors=Jones DS, Jones JH|date=2014-12-01|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|volume=60|pages=5–22|doi=10.1098/rsbm.2014.0002|s2cid=71557916|issn=0080-4606|doi-access=|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 was later confirmed in 1945 using [[X-ray crystallography]] by [[Dorothy Hodgkin|Dorothy Crowfoot Hodgkin]], who was also working at Oxford.<ref>{{cite web |title=The Nobel Prize in Chemistry 1964 |url=https://www.nobelprize.org/prizes/chemistry/1964/perspectives/ |website=NobelPrize.org |access-date=9 May 2022 |archive-url=https://web.archive.org/web/20170716001027/http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1964/perspectives.html |archive-date=2017-07-16}}</ref> She later in 1964 received the Nobel Prize for Chemistry for this and other structure determinations.

Chemist [[John C. Sheehan]] at the [[Massachusetts Institute of Technology]] (MIT) completed the first chemical [[total synthesis|synthesis]] of penicillin in 1957.<ref name=Sheehan1957>{{cite journal| vauthors = Sheehan JC, Henery-Logan KR |title=The Total Synthesis of Penicillin V|journal=Journal of the American Chemical Society|date=March 5, 1957|volume=79|issue=5|pages=1262–63|doi=10.1021/ja01562a063|bibcode=1957JAChS..79.1262S }}</ref><ref name=Sheehan1959>{{cite journal| vauthors = Sheehan JC, Henery-Loganm KR |title=The Total Synthesis of Penicillin V|journal=Journal of the American Chemical Society|date=June 20, 1959|volume=81|issue=12|pages=3089–94|doi=10.1021/ja01521a044|bibcode=1959JAChS..81.3089S }}</ref><ref name=NAPSheehan>{{cite web|title=Biographical Memoirs: John Clark Sheehan|url=http://www.nap.edu/readingroom.php?book=biomems&page=jsheehan.html|publisher=The National Academy Press|access-date=January 28, 2013|vauthors=Corey EJ, Roberts JD|author-link1=Elias James Corey|author-link2=John D. Roberts|archive-date=March 3, 2016|archive-url=https://web.archive.org/web/20160303213006/http://www.nap.edu/readingroom.php?book=biomems|url-status=live}}</ref> Sheehan had started his studies into penicillin synthesis in 1948, and during these investigations developed new methods for the synthesis of [[peptides]], as well as new [[protecting group]]s—groups that mask the reactivity of certain functional groups.<ref name=NAPSheehan /><ref name=ArtTotalSyn>{{cite journal | vauthors = Nicolaou KC, Vourloumis D, Winssinger N, Baran PS | title = The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century | journal = Angewandte Chemie | volume = 39 | issue = 1 | pages = 44–122 | date = January 2000 | pmid = 10649349 | doi = 10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L | author-link4 = Phil S. Baran | author-link1 = K. C. Nicolaou }}</ref> Although the initial synthesis developed by Sheehan was not appropriate for mass production of penicillins, one of the intermediate compounds in Sheehan's synthesis was 6-aminopenicillanic acid (6-APA), the nucleus of penicillin.<ref name="Sheehan1957" /><ref name="Sheehan1959" /><ref name=NAPSheehan /><ref name=MITSheehan>{{cite news|title=Professor John C. Sheehan Dies at 76|url=http://web.mit.edu/newsoffice/1992/sheehan-0401.html|access-date=January 28, 2013|newspaper=MIT News|date=April 1, 1992|archive-date=June 30, 2008|archive-url=https://web.archive.org/web/20080630091223/http://web.mit.edu/newsoffice/1992/sheehan-0401.html|url-status=live}}</ref>

6-APA was discovered by researchers at the Beecham Research Laboratories (later the [[Beecham Group]]) in Surrey in 1957 (published in 1959).<ref>{{cite journal | vauthors = Batchelor FR, Doyle FP, Nayler JH, Rolinson GN | title = Synthesis of penicillin: 6-aminopenicillanic acid in penicillin fermentations | journal = Nature | volume = 183 | issue = 4656 | pages = 257–58 | date = January 1959 | pmid = 13622762 | doi = 10.1038/183257b0 | s2cid = 4268993 | bibcode = 1959Natur.183..257B }}</ref> Attaching different groups to the 6-APA 'nucleus' of penicillin allowed the creation of new forms of penicillins which are more versatile and better in activity.<ref>{{cite journal | vauthors = Rolinson GN, Geddes AM | title = The 50th anniversary of the discovery of 6-aminopenicillanic acid (6-APA) | journal = International Journal of Antimicrobial Agents | volume = 29 | issue = 1 | pages = 3–8 | date = January 2007 | pmid = 17137753 | doi = 10.1016/j.ijantimicag.2006.09.003 }}</ref>

=== Developments from penicillin ===
The narrow range of treatable diseases or "spectrum of activity" of the penicillins, along with the poor activity of the orally active phenoxymethylpenicillin, led to the search for derivatives of penicillin that could treat a wider range of infections. The isolation of 6-APA, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin (bioavailability, spectrum, stability, tolerance).

The first major development was ampicillin in 1961. It offered a broader spectrum of activity than either of the original penicillins. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin, dicloxacillin, and methicillin. These were significant for their activity against β-lactamase-producing bacterial species, but were ineffective against the [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']] (MRSA) strains that subsequently emerged.<ref>{{cite journal | vauthors = Colley EW, Mcnicol MW, Bracken PM | title = Methicillin-Resistant Staphylococci in a General Hospital | journal = Lancet | volume = 1 | issue = 7385 | pages = 595–97 | date = March 1965 | pmid = 14250094 | doi = 10.1016/S0140-6736(65)91165-7 }}</ref>

Another development of the line of true penicillins was the antipseudomonal penicillins, such as carbenicillin, ticarcillin, and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the β-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems, and, most important, the cephalosporins, still retain it at the center of their structures.<ref>{{cite journal | vauthors = James CW, Gurk-Turner C | title = Cross-reactivity of beta-lactam antibiotics | journal = Proceedings | volume = 14 | issue = 1 | pages = 106–07 | date = January 2001 | pmid = 16369597 | pmc = 1291320 | doi = 10.1080/08998280.2001.11927741 }}</ref>