Examine individual changes

'{{For|the Japanese band|Penicillin (band)}} {{pp-move-indef}} [[Image:Penicillin core.svg|thumb|250px|Penicillin core structure. The "R" is the variable group.]] '''Penicillin''' (sometimes abbreviated '''PCN''' or '''pen''') is a group of [[antibiotic]]s derived from ''[[Penicillium]]'' fungi.<ref>{{DorlandsDict|six/000079881|penicillin}}</ref> Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases such as [[syphilis]] and [[Staphylococcus]] infections. Penicillins are still widely used today, though many types of [[bacteria]] are now [[antibiotic resistance|resistant]]. All penicillins are [[Beta-lactam antibiotic]]s and are used in the treatment of [[bacteria]]l [[infection]]s caused by susceptible, usually [[Gram-positive]], organisms. The term "penicillin" can also refer to the ''mixture'' of substances that are naturally, and organically, produced.<ref name="urlpenicillin - Definition from Merriam-Websters Medical Dictionary">{{cite web |url=http://medical.merriam-webster.com/medical/penicillin |title=penicillin - Definition from Merriam-Webster's Medical Dictionary |format= |work= |accessdate=2009-01-02}}</ref> ==Structure== [[Image:Penicillin-nucleus-3D-balls.png|thumb|Penicillin core structure, in 3D. Purple areas are variable groups.]] The term "[[penam]]" is used to describe the core skeleton of a member of a penicillin antibiotic. This skeleton has the molecular formula R-C₉H₁₁N₂O₄S, where R is a variable [[side chain]]. Normal penicillin has a [[molecular weight]] of 313<ref>[http://www.learnchem.net/tutorials/stoich.shtml learnchem.net Stoichiometry] Section: Percent Mass. By Takalah. Retrieved on Jan 9, 2009</ref> to 334<ref>[http://drugsafetysite.com/penicillin-g-benzathine/ Drug Safety > Penicillin G] Retrieved on Jan 9, 2009</ref><ref>[http://www.symplus.com/legacy/biowiki/en/penicillin SymplusWiki > penicillin G] Retrieved on Jan 9, 2009</ref> g/mol (latter for penicillin G). Penicillin types with additional molecular groups attached may have a molar mass around 500 g/mol. For example, [[cloxacillin]] has a molar mass of 476 g/mol and [[dicloxacillin]] has a molar mass of 492 g/mol.<ref> {{cite journal | title = Complexes of penicillins and human serum albumin studied by static light scattering | year = 2003 | month = August | author = Barbosa S., Taboada P., Ruso J.M., Attwood D., Mosquera V. | journal = Colloids and Surfaces A: Physicochemical and Engineering Aspects | issues = 1-3 | pages = 251–6 | doi = 10.1016/S0927-7757(03)00322-4 | volume = 224 }}</ref> ==Biosynthesis== [[Image:Penicillin-biosynthesis.png|thumb|Penicillin biosynthesis.]] Overall, there is a total of three main and important steps to the biosynthesis of [[penicillin G]] (benzylpenicillin) *The first step in the biosynthesis of penicillin G is the condensation of three amino acids <small>L</small>-α-aminoadipic acid, <small>L</small>-cysteine, <small>L</small>-valine into a [[tripeptide]].<ref name ="Regulation"> {{cite book | title = Molecular Biotechnolgy of Fungal beta-Lactam Antibiotics and Related Peptide Synthetases | editor = Brakhage AA | author = Al-Abdallah, Q., Brakhage, A. A., Gehrke, A., Plattner, H., Sprote, P., Tuncher, A. | chapter = Regulation of Penicillin Biosynthesis in Filamentous Fungi | year = 2004 | issue = 88 | pages = 45–90 | doi = 10.1007/b99257 | isbn = 3-540-22032-1 }}</ref><ref name=Molecular> {{cite journal | author = Brakhage, A. A. | title = Molecular Regulation of b-Lactam Biosynthesis in Filamentous Fungi | journal = Microbiol Mol Biol Rev. | year = 1998 | issue = 62 | pages = 547–85 }}</ref><ref> {{cite journal | author = Baldwin, J. E., Byford, M. F., Clifton, I., Hajdu, J., Hensgens, C., Roach, P, Schofield, C. J. | title = Proteins of the Penicillin Biosynthesis Pathway | journal = Curr Opin Struct Biol. | year = 1997 | issue = 7 | pages = 857–64 }}</ref> Before condensing into a tripeptide, the amino acid L-valine will undergo epimerization and become D-valine.<ref name=Fern> {{cite journal | author= Fernandez, F. J., Fierro, F., Gutierrez, S, Kosalkova, K . Marcos, A. T., Martin, J. F., Velasco, J. | title = Expression of Genes and Processing of Enzymes for the Biosynthesis of Penicillins and Cephalosporms | journal = Anton Van Lee | year = 1994 | month = September | volume = 65 | issue = 3 | pages = 227–43 | doi= 10.1007/BF00871951 }}</ref><ref>Baker, W. L., Lonergan, G. T. "Chemistry of Some Fluorescamine-Amine Derivatives with Relevance to the Biosynthesis of Benzylpenicillin by Fermentation". J Chem Technol Biot. 2002, 77, pp1283-1288.</ref> After the condensation, the tripeptide is named δ-(L-α-aminoadipyl)-L-cysteine-D-valine, which is also known as ACV. While this reaction occurs, we must add in a required catalytic enzyme ACVS, which is also known as δ-(L-α-aminoadipyl)-L-cysteine-D-valine synthetase. This catalytic enzyme ACVs is required for the activation of the three amino acids before condensation and the epimerization of transforming L-valine to D-valine.<br/> *The second step in the biosynthesis of penicillin G is to use an enzyme to change ACV into isopenicillin N. The enzyme is isopenicillin N synthase with the gene pcbC enclosed. The tripeptide on the ACV will then undergo oxidation, which then allows a ring closure so that a bicyclic ring is formed.<ref name ="Regulation" /><ref name=Molecular/> Isopenicillin N is a very weak intermediate because it does not show much antibiotic activity.<ref name=Fern/> *The Last step in the biosynthesis of penicillin G is the exchange the side-chain group so that isopenicillin N will become penicillin G. Through the catalytic coenzyme isopenicillin N acyltransferase (IAT), the alpha-aminoadipyl side-chain of isopenicillin N is removed and exchanged for a phenylacetyl side-chain. This reaction is encoded by the gene penDE, which is unique in the process of obtaining penicillins.<ref name ="Regulation" /> ==History== ===Discovery=== {{Main|History of penicillin}} The discovery of penicillin is attributed to [[Scotland|Scottish]] scientist and Nobel laureate [[Alexander Fleming]] in 1928.<ref>{{cite web | title = Alexander Fleming – Time 100 People of the Century | url = http://205.188.238.181/time/time100/scientist/profile/fleming.html | work = [[Time (magazine)|Time]] | accessdate = | quote = It was a discovery that would change the course of history. The active ingredient in that mold, which Fleming named penicillin, turned out to be an infection-fighting agent of enormous potency. When it was finally recognized for what it is — the most efficacious life-saving drug in the world — penicillin would alter forever the treatment of bacterial infections.}}</ref> He showed that, if ''[[Penicillium notatum]]'' was grown in the appropriate substrate, it would exude a substance with antibiotic properties, which he dubbed penicillin. This [[serendipity|serendipitous]] observation began the modern era of antibiotic discovery. The development of penicillin for use as a medicine is attributed to the Australian Nobel laureate [[Howard Walter Florey]] together with the German Nobel laureate [[Ernst Chain]] and the English biochemist [[Norman Heatley]]. However, several others reported the bacteriostatic effects of ''Penicillium'' earlier than Fleming. The use of bread with a blue mould (presumably penicillium) as a means of treating suppurating wounds was a staple of folk medicine in Europe since the Middle Ages. The first published reference appears in the publication of the [[Royal Society]] in 1875, by [[John Tyndall]].<ref>Phil. Trans., 1876, 166, pp27-74. Referred to at: [[Discoveries of anti-bacterial effects of penicillium moulds before Fleming]]</ref> [[Ernest Duchesne]] documented it in an 1897 paper, which was not accepted by the Institut Pasteur because of his youth. In March 2000, doctors at the [[San Juan De Dios Educational Foundation|San Juan de Dios Hospital]] in San José, Costa Rica published the manuscripts of the Costa Rican scientist and medical doctor [[Clodomiro Picado Twight|Clodomiro (Clorito) Picado Twight]] (1887–1944). They reported Picado's observations on the inhibitory actions of fungi of the genus ''Penicillium'' between 1915 and 1927. Picado reported his discovery to the [[French Academy of Sciences|Paris Academy of Sciences]], yet did not patent it, even though his investigations started years before Fleming's. Joseph Lister was experimenting with penicillum in 1871 for his Aseptic surgery. He found that it weakened the microbes but then he dismissed the fungi. Fleming recounted that the date of his discovery of penicillin was on the morning of Friday, September 28, 1928.<ref>{{cite book |author=Haven, Kendall F. |title=Marvels of Science : 50 Fascinating 5-Minute Reads |publisher=Libraries Unlimited |location=Littleton, Colo |year=1994 |pages=182 |isbn=1-56308-159-8 }}</ref> It was a fortuitous accident: in his laboratory in the basement of St. Mary's Hospital in [[London]] (now part of [[Imperial College]]), Fleming noticed a petri dish containing ''[[Staphylococcus]]'' plate culture he had mistakenly left open, which was contaminated by blue-green [[mould]], which had formed a visible growth. There was a halo of inhibited bacterial growth around the mould. Fleming concluded that the mould was releasing a substance that was repressing the growth and [[lysis|lysing]] the bacteria. He grew a pure culture and discovered that it was a ''[[Penicillium]]'' mould, now known to be ''Penicillium notatum''. [[Charles Thom]], an American specialist working at the U.S. Department of Agriculture, was the acknowledged expert, and Fleming referred the matter to him. Fleming coined the term "penicillin" to describe the [[filtrate]] of a broth [[microbiological culture|culture]] of the ''Penicillium'' mould. Even in these early stages, penicillin was found to be most effective against [[Gram-positive]] bacteria, and ineffective against [[Gram-negative]] organisms and fungi. He expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, and noted its laboratory value in the isolation of "''Bacillus influenzae''" (now ''[[Haemophilus influenzae]]'').<ref name="Flemming1929">{{cite journal | author=Fleming A. | title=On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of ''B. influenzæ'' | journal=Br J Exp Pathol | year=1929 | volume=10 | issue=31 | pages=226–36}}</ref> After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria, and stopped studying it after 1931. He restarted [[clinical trials]] in 1934, and continued to try to get someone to purify it until 1940.<ref name="Brown2004">{{cite book | author= Brown, Kevin. | title=Penicillin Man: Alexander Fleming and the Antibiotic Revolution. | location=Stroud | publisher=Sutton | year=2004 | isbn = 0-7509-3152-3}}</ref> ===Medical application=== In 1930, Cecil George Paine, a [[pathologist]] at the Royal Infirmary in Sheffield, attempted to use penicillin to treat [[sycosis barbae]]–eruptions in beard follicles, but was unsuccessful, probably because the drug did not penetrate the skin deeply enough. Moving on to [[Neonatal conjunctivitis|ophthalmia neonatorum]]; a gonococcal infection in infants, he achieved the first recorded cure with penicillin, on November 25, 1930. He then cured four additional patients (one adult and three infants) of eye infections, failing to cure a fifth.<ref name="Wainwright, M & Swan, HT 1986 42–56"> {{cite journal | author = 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 | year = 1986 | month = January | pmid = 3511336 | pmc = 1139580 | doi = | url = | issn = | accessdate = 2010-03-15 }}</ref> In 1939, Australian scientist [[Howard Walter Florey|Howard Florey]] (later Baron Florey) and a team of researchers ([[Ernst Boris Chain]], [[A. D. Gardner]], [[Norman Heatley]], M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, [[University of Oxford]] made significant progress in showing the ''[[in vivo]]'' bactericidal action of penicillin. Their attempts to treat humans failed due to insufficient volumes of penicillin (the first patient treated was [[Albert Alexander|Reserve Constable Albert Alexander]]), but they proved it harmless and effective on mice.<ref> {{cite journal |last=Drews |first=Jürgen |year=2000 |month=March |title=Drug Discovery: A Historical Perspective |journal=Science |volume=287 |issue=5460 |pages=1960–4 |doi=10.1126/science.287.5460.1960 |pmid=10720314}}</ref> Some of the pioneering trials of penicillin took place at the [[Radcliffe Infirmary]] in Oxford, England. These trials continue to be cited by some sources as the first cures using penicillin, though the Paine trials took place earlier.<ref name="Wainwright, M & Swan, HT 1986 42–56"/> On March 14, 1942, John Bumstead and [[Orvan Hess]] saved a dying patient's life using penicillin.<ref>{{cite news | author=Saxon, W. | url=http://www.nytimes.com/1999/06/09/us/anne-miller-90-first-patient-who-was-saved-by-penicillin.html | title=Anne Miller, 90, first patient who was saved by penicillin | work=[[The New York Times]] | date=June 9, 1999}}</ref><ref>{{cite web | author=Krauss K, editor | title=Yale-New Haven Hospital Annual Report | url=http://www.ynhh.org/general/annreport/ynhh99ar.pdf | format=PDF | year=1999 | publisher=Yale-New Haven Hospital | location=New Haven}}</ref> ===Mass production=== The [[chemical structure]] of penicillin was determined by [[Dorothy Hodgkin|Dorothy Crowfoot Hodgkin]] in 1945. Penicillin has since become the most widely used antibiotic to date, and is still used for many [[Gram-positive]] bacterial infections. A team of Oxford research scientists led by Australian [[Howard Florey, Baron Florey|Howard Florey]] and including [[Ernst Boris Chain]] and [[Norman Heatley]] devised a method of mass-producing the drug. Florey and Chain shared the 1945 [[Nobel Prize in Physiology or Medicine|Nobel prize in medicine]] with Fleming for their work. After World War II, [[Australia]] was the first country to make the drug available for civilian use. Chemist [[John C. Sheehan]] at [[MIT]] completed the first [[total synthesis]] of penicillin and some of its analogs in the early 1950s, but his methods were not efficient for mass production. The challenge of mass-producing this drug was daunting. On March 14, 1942, the first patient was treated for streptococcal septicemia with U.S.-made penicillin produced by [[Merck & Co.]]<ref>[http://www.annals.org/cgi/content/full/149/2/135 The First Use of Penicillin in the United States], by Charles M. Grossman. ''[[Annals of Internal Medicine]]'' 15 July 2008: Volume 149, Issue 2, Pages 135-136.</ref> Half of the total supply produced at the time was used on that one patient. By June 1942, there was just enough U.S. penicillin available to treat ten patients.<ref>{{cite web | author=John S. Mailer, Jr., and Barbara Mason |url=http://www.lib.niu.edu/ipo/2001/iht810139.html |title=Penicillin : Medicine's Wartime Wonder Drug and Its Production at Peoria, Illinois | publisher=lib.niu.edu | accessdate=2008-02-11}}</ref> A moldy [[cantaloupe]] in a Peoria, Illinois market in 1943 was found to contain the best and highest-quality penicillin after a worldwide search.<ref>{{cite web |author=Mary Bellis |title=The History of Penicillin |url=http://inventors.about.com/od/pstartinventions/a/Penicillin.htm |work=Inventors |publisher=About.com |accessdate=2007-10-30}}</ref> The discovery of the cantaloupe, and the results of fermentation research on [[corn steep liquor]] at the Northern Regional Research Laboratory at Peoria, Illinois, allowed the United States to produce 2.3 million doses in time for the [[invasion of Normandy]] in the spring of 1944. Large-scale production resulted from the development of deep-tank fermentation by chemical engineer [[Margaret Hutchinson Rousseau]].<ref name=ChemH>[http://www.chemheritage.org/women_chemistry/med/rousseau.html Chemical Heritage] Manufacturing a Cure: Mass Producing Penicillin</ref> [[Image:PenicillinPSAedit.jpg|thumb|right|300px|Penicillin was being mass-produced in 1944.]] G. Raymond Rettew made a significant contribution to the American war effort by his techniques to produce commercial quantities of penicillin.<ref> {{cite web |url=http://explorepahistory.com/hmarker.php?markerId=974 |title=ExplorePAhistory.com |publisher= |accessdate=2009-05-11 |last= |first= }} </ref> 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.{{Citation needed|date=February 2008}} 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. 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 | author=Silverthorn, DU. | title=Human physiology: an integrated approach. | edition=3rd | location=Upper Saddle River (NJ) | publisher=Pearson Education | year=2004 | isbn=0-8053-5957-5}}</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 name=AMH2006>{{cite book | editor=Rossi S, editor | title=[[Australian Medicines Handbook]] | year=2006 | location=Adelaide | publisher=Australian Medicines Handbook | isbn=0-9757919-2-3}}</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]], which offered a broader spectrum of activity than either of the original penicillins. Further development yielded [[beta-lactamase]]-resistant penicillins including [[flucloxacillin]], [[dicloxacillin]] and [[methicillin]]. These were significant for their activity against beta-lactamase-producing bacteria species, but are ineffective against the [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']] strains that subsequently emerged. 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 beta-lactam ring was such that related antibiotics, including the [[mecillinam]]s, the [[carbapenem]]s and, most important, the [[cephalosporin]]s, still retain it at the center of their structures.<ref> {{cite journal | last = James, PharmD | first = Christopher W. | coauthors = Cheryle Gurk-Turner, RPh | title = Cross-reactivity of beta-lactam antibiotics | journal = Baylor University Medical Center Proceedings | volume = 14 | issue = 1 | pages = 106–7 | publisher = Baylor University Medical Center | location = Dallas, Texas |pmc=1291320 | accessdate = 2007-11-17 | pmid = 16369597 | date = 2001 January}}</ref> ==Mechanism of action== {{Main|Beta-lactam antibiotic}} β-Lactam antibiotics work by inhibiting the formation of [[peptidoglycan]] [[cross-link]]s in the bacterial [[cell wall]]. The [[beta-lactam|β-lactam]] moiety ([[functional group]]) of penicillin binds to the [[enzyme]] ([[DD-transpeptidase]]) that links the peptidoglycan molecules in bacteria, which weakens the cell wall of the bacterium (in other words, the antibiotic causes [[cytolysis]] or death due to [[osmotic]] pressure). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the bacteria's existing peptidoglycan. [[Gram-positive]] bacteria are called [[protoplast]]s when they lose their cell wall. [[Gram-negative]] bacteria do not lose their cell wall completely and are called [[spheroplast]]s after treatment with penicillin. Penicillin shows a synergistic effect with [[aminoglycosides]], since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing its disruption of bacterial protein synthesis within the cell. This results in a lowered [[Minimum Bactericidal Concentration|MBC]] for susceptible organisms. Penicillins, like other [[beta-lactam|β-lactam]] antibiotics, block not only the division of bacteria, including [[cyanobacteria]], but also the division of cyanelles, the [[Photosynthesis|photosynthetic]] [[organelle]]s of the [[glaucophyte]]s, and the division of [[chloroplast]]s of [[bryophyte]]s. In contrast, they have no effect on the [[plastid]]s of the highly developed [[vascular plant]]s. This supports the [[endosymbiotic theory]] of the [[evolution]] of plastid division in land [[plant]]s.<ref>{{cite journal|first1=Britta|last1=Kasten|first2=Ralf|last2=Reski|link2=[[Ralf Reski]]|date=30 March 1997|title=β-lactam antibiotics inhibit chloroplast division in a moss (Physcomitrella patens) but not in tomato (Lycopersicon esculentum)|journal=Journal of Plant Physiology|volume=150|pages=137–140|url=http://cat.inist.fr/?aModele=afficheN&cpsidt=2640663|issue=1-2}}</ref> ==Variants in clinical use== The term "penicillin" is often used in the generic sense to refer to one of the narrow-spectrum penicillins, in particular, [[benzylpenicillin]] (penicillin G). Other types include: * [[Phenoxymethylpenicillin]] * [[Procaine benzylpenicillin]] * [[Benzathine benzylpenicillin]] * [[Benzylpenicillin potassium]] <ref name=ibp2009>{{cite web | last = British Pharmacopoeia Commission Secretariat | first = | authorlink = | coauthors = | title = Index (BP 2009) | work = | publisher = | date = | url = http://www.pharmacopoeia.co.uk/pdf/2009_index.pdf | doi = | accessdate = 26 March 2010 }}</ref> {{Clarify|date=March 2010}} * [[Benzylpenicillin sodium]] <ref name=ibp2009 /> * [[Phenoxymethylpenicillin potassium]] <ref name=ibp2009 /> ==Adverse effects== {{main|Penicillin drug reaction}} Common [[adverse drug reaction]]s (≥1% of patients) associated with use of the penicillins include [[diarrhea]], [[hypersensitivity]], [[nausea]], rash, [[neurotoxicity]], [[urticaria]], and [[superinfection]] (including [[candidiasis]]). Infrequent adverse effects (0.1–1% of patients) include fever, vomiting, [[erythema]], [[dermatitis]], [[angioedema]], [[seizures]] (especially in epileptics), and [[pseudomembranous colitis]].<ref name="AMH2006" /> ==Production== Penicillin is a [[Secondary metabolism|secondary metabolite]] of fungus ''[[Penicillium]]'' that is produced when growth of the fungus is inhibited by stress. It is not produced during active growth. Production is also limited by feedback in the synthesis pathway of penicillin. ::α-ketoglutarate + AcCoA → homocitrate → L-α-aminoadipic acid → L-Lysine + β-lactam The by-product L-Lysine inhibits the production of homocitrate, so the presence of exogenous lysine should be avoided in penicillin production. The Penicillium cells are grown using a technique called [[fed-batch]] culture, in which the cells are constantly subject to stress and will produce plenty of penicillin. The carbon sources that are available are also important: Glucose inhibits penicillin, whereas lactose does not. The pH and the levels of nitrogen, lysine, phosphate, and oxygen of the batches must be controlled automatically. Penicillin production emerged as an industry as a direct result of World War II. During the war, there was an abundance of jobs available in the U.S. on the home front. The [[War Production Board]] was founded to monitor job distribution and production.<ref>"[http://history.howstuffworks.com/world-war-ii/start-world-war-2.htm Start of World War II.]" Legacy Publishers. 2 Apr. 2008</ref> Penicillin was produced in huge quantities during the war and the industry prospered. In July 1943, the War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe. At the time of this plan, 425 million units per year were being produced. As a direct result of the war and the War Production Board, by June 1945 over 646 billion units per year were being produced.<ref>{{cite book |author=Parascandola, John |title=The History of antibiotics: a symposium |publisher=American Institute of the History of Pharmacy No. 5 |year=1980 |isbn=0-931292-08-5 }}</ref> In recent years, the [[biotechnology]] method of [[directed evolution]] has been applied to produce by mutation a large number of Penicillium strains. These directed-evolution techniques include error-prone [[PCR]], [[DNA]] shuffling, ITCHY, and strand overlap PCR. ==See also== {{Commons category|Penicillin antibiotics}} * [[Beta-lactam antibiotic|β-Lactam antibiotic]] * [[Drug allergy]] * [[Kay's Tutor v Ayrshire & Arran Health Board]] * [[Medicinal mushrooms]] * [[Penicillinase]] ==References== {{reflist|2}} ==External links== * [http://users.ox.ac.uk/~jesu1458/ Model of Structure of Penicillin, by Dorothy Hodgkin et al., Museum of the History of Science, Oxford] * [http://www.youtube.com/watch?v=7qeZLLhx5kU The Discovery of Penicillin, A government produced film about the discovery of Penicillin by Sir Alexander Fleming, and the continuing development of its use as an antibiotic by Howard Florey and Ernst Boris Chain.] {{PenicillinAntiBiotics}} {{GABAergics}} [[Category:Beta-lactam antibiotics]] [[Category:Eli Lilly and Company]] [[Category:Scottish inventions]] [[Category:Microbiology]] [[Category:Science and technology during World War II]] {{Link GA|eo}} {{Link FA|es}} {{Link FA|sr}} [[af:Penisillien]] [[ar:بنسلين]] [[an:Penicilina]] [[bn:পেনিসিলিন]] [[bs:Penicilin]] [[bg:Пеницилин]] [[ca:Penicil·lina]] [[cs:Penicilin]] [[da:Penicillin]] [[de:Penicillin]] [[et:Penitsilliin]] [[el:Πενικιλίνη]] [[es:Penicilina]] [[eo:Penicilino]] [[eu:Penizilina]] [[fa:پنی‌سیلین]] [[fo:Penicillin]] [[fr:Pénicilline]] [[fy:Penisilline]] [[ko:페니실린]] [[hi:पेनिसिलिन]] [[hr:Penicilin]] [[io:Penicilino]] [[id:Penisilin]] [[is:Penisillín]] [[it:Penicillina]] [[he:פניצילין]] [[ka:პენიცილინი]] [[kk:Пенициллин]] [[ht:Penisilin]] [[la:Penicillinum]] [[lt:Penicilinas]] [[hu:Penicillin]] [[ml:പെനിസിലിൻ]] [[mr:पेनिसिलिन]] [[arz:بينسيلين]] [[nl:Penicilline]] [[ja:ペニシリン]] [[no:Penicillin]] [[nn:Penicillin]] [[oc:Penicillina]] [[pnb:پنسلین]] [[pl:Penicyliny]] [[pt:Penicilina]] [[ro:Penicilină]] [[ru:Бензилпенициллин]] [[simple:Penicillin]] [[sk:Penicilín]] [[sl:Penicilini]] [[sr:Пеницилин]] [[fi:Penisilliini]] [[sv:Penicillin]] [[ta:பெனிசிலின்]] [[te:పెన్సిలిన్]] [[th:เพนิซิลลิน]] [[tr:Penisilin]] [[uk:Пеніцилін]] [[vi:Penicillin]] [[war:Penicillin]] [[zh:青霉素]]'