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Penicillin

Penicillin core structure, where "R" is the variable group.

Penicillin (sometimes abbreviated PCN or pen) is agroup of antibiotics derived from Penicillium fungi.[1]

They include penicillin G, procaine penicillin,benzathine penicillin, and penicillin V. Penicillinantibiotics are historically significant because they arethe first drugs that were effective against manypreviously serious diseases, such as syphilis, andinfections caused by staphylococci and streptococci.Penicillins are still widely used today, though manytypes of bacteria are now resistant. All penicillins areβ-lactam antibiotics and are used in the treatment ofbacterial infections caused by susceptible, usually Gram-positive, organisms.

Medical usesThe term "penicillin" is often used generically to refer to benzylpenicillin (penicillin G), procaine benzylpenicillin(procaine penicillin), benzathine benzylpenicillin (benzathine penicillin), and phenoxymethylpenicillin (penicillinV).Procaine penicillin and benzathine penicillin have the same antibacterial activity as benzylpenicillin but act for alonger time span. Phenoxymethylpenicillin is less active against Gram-negative bacteria than benzylpenicillin.[2][3]

Benzylpenicillin, procaine penicillin and benzathine penicillin are given by injection (parenterally), butphenoxymethylpenicillin is given orally.

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Adverse effectsCommon adverse drug reactions (≥1% of patients) associated with use of the penicillins include diarrhoea,hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection (including candidiasis). Infrequent adverseeffects (0.1–1% of patients) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially inepileptics), and pseudomembranous colitis.[4]

Mechanism of action

Penicillin and other β-lactamantibiotics act by inhibiting

penicillin-binding proteins, whichnormally catalyze cross-linking of

bacterial cell walls.

Bacteria constantly remodel their peptidoglycan cell walls, simultaneouslybuilding and breaking down portions of the cell wall as they grow and divide.β-Lactam antibiotics inhibit the formation of peptidoglycan cross-links in thebacterial cell wall, but have no direct effect on cell wall degradation. Theβ-lactam moiety (functional group) of penicillin binds to the enzyme(DD-transpeptidase) that links the peptidoglycan molecules in bacteria. Theenzymes that hydrolyze the peptidoglycan cross-links continue to function,which weakens the cell wall of the bacterium (in other words, the antibioticcauses cytolysis or death due to osmotic pressure). In addition, the build-up ofpeptidoglycan precursors triggers the activation of bacterial cell wall hydrolasesand autolysins, which further digest the bacteria's existing peptidoglycan. Thisimbalance between cell wall production and degradation is responsible for therapid cell-killing action of this class of drugs, even in the absence of celldivision. In addition, the relatively small size of the penicillin molecule allows itto penetrate deeply into the cell wall, affecting its entire depth. This is in contrastto the other major class of anitbiotics that inhibit cell wall synthesis, theglycopeptide antibiotics (which includes vancomycin and teicoplanin).

Gram-positive bacteria are called protoplasts when they lose their cell walls.Gram-negative bacteria do not lose their cell walls completely and are called spheroplasts after treatment withpenicillin.

Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allowsaminoglycosides to penetrate the bacterial cell wall more easily, allowing their disruption of bacterial proteinsynthesis within the cell. This results in a lowered MBC for susceptible organisms.

Penicillins, like other β-lactam antibiotics, block not only the division of bacteria, including cyanobacteria, but alsothe division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts ofbryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This supports theendosymbiotic theory of the evolution of plastid division in land plants.[5]

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Bacteria that attempt to divide in thepresence of penicillin fail to do so

and end up shedding their cell wallsin the process.

Structure

Chemical structure of Penicillin G

The term "penam" is used to describe the core skeleton of a member ofthe penicillin antibiotics. This skeleton has the molecular formulaR-C9H11N2O4S, where R is a variable side chain.

Normal penicillin has a molecular weight of 313[6] to 334[7][8] g/mol(latter for penicillin G). Penicillin types with additional moleculargroups attached may have a molar mass around 500 g/mol. Forexample, cloxacillin has a molar mass of 476 g/mol and dicloxacillin

has a molar mass of 492 g/mol.[9]

Penicillin 4

Penicillin core structure, in 3D. Purple areas arevariable groups.

Biosynthesis

Penicillin biosynthesis

Overall, there are three main and important steps to the biosynthesis ofpenicillin G (benzylpenicillin).

• The first step is the condensation of three amino acids —L-α-aminoadipic acid, L-cysteine, L-valine into atripeptide.[10][11][12] Before condensing into the tripeptide, theamino acid L-valine must undergo epimerization to becomeD-valine.[13][14] The condensed tripeptide is namedδ-(L-α-aminoadipyl)-L-cysteine-D-valine (ACV). The condensationreaction and epimerization are both catalyzed by the enzymeδ-(L-α-aminoadipyl)-L-cysteine-D-valine synthetase (ACVS), anonribosomal peptide synthetase or NRPS.

• The second step in the biosynthesis of penicillin G is the oxidativeconversion of linear ACV into the bicyclic intermediateisopenicillin N by isopenicillin N synthase (IPNS), which isencoded by the gene pcbC.[10][11] Isopenicillin N is a very weakintermediate, because it does not show strong antibiotic activity.[13]

• The final step is an transamidation by isopenicillin N N-acyltransferase, in which the α-aminoadipyl side-chain ofisopenicillin N is removed and exchanged for a phenylacetyl side-chain. This reaction is encoded by the genepenDE, which is unique in the process of obtaining penicillins.[10]

ProductionPenicillin is a secondary metabolite of certain species of Penicillium and is produced when growth of the fungus isinhibited by stress. It is not produced during active growth. Production is also limited by feedback in the synthesispathway of penicillin.

α-ketoglutarate + AcCoA → homocitrate → L-α-aminoadipic acid → L-lysine + β-lactamThe by-product, l-lysine, inhibits the production of homocitrate, so the presence of exogenous lysine should beavoided in penicillin production.The Penicillium cells are grown using a technique called fed-batch culture, in which the cells are constantly subjectto stress, which is required for induction of penicillin production. The available carbon sources are also important:Glucose inhibits penicillin production, whereas lactose does not. The pH and the levels of nitrogen, lysine,phosphate, and oxygen of the batches must also be carefully controlled.

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The biotechnological method of directed evolution has been applied to produce by mutation a large number ofPenicillium strains. These techniques include error-prone PCR, DNA shuffling, ITCHY, and strand-overlap PCR.Semisynthetic penicillins are prepared starting from the penicillin nucleus 6-APA.

History

DiscoveryThe discovery of penicillin is attributed to Scottish scientist and Nobel laureate Alexander Fleming in 1928.[15] Heshowed that, if Penicillium rubens[16] were grown in the appropriate substrate, it would exude a substance withantibiotic properties, which he dubbed penicillin. This serendipitous observation began the modern era of antibioticdiscovery. The development of penicillin for use as a medicine is attributed to the Australian Nobel laureate HowardWalter 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 witha blue mould (presumed to be Penicillium) as a means of treating suppurating wounds was a staple of folk medicinein Europe since the Middle Ages.The first published reference appears in the publication of the Royal Society in 1875, by John Tyndall.[17] JoaquimMonteiro Caminhoá, Professor of Botany and Zoology of the Faculty of Medicine of Rio de Janeiro, Brazil, alsorecognised the antibiotic activity of Penicillium and other fungi in 1877. In his book, "Elements of General andMedical Botany" (under a section titled 'Useful fungi, harmful and curious'), he stated:

O bolor (Penicillium infestans, Penicillium glaucum, fig 1680, Ascophora e tantos outros) é util porquenutre-se decompondo e destruindo as materias organicas em putrefacção, e de modo que o cheiro infecto nãose produz, em via de regra, ou produz-se em proporções infinitamente menores.

[Translation: "The mould (Penicillium infestans, Penicillium glaucum, figure 1680, Ascophora and manyothers) is useful because it feeds on decaying organic matter and destroys putrifaction so that, as a rule, theodour of infection does not occur, or is produced in infinitely smaller amounts."][18]

In 1895, Vincenzo Tiberio, physician of the University of Naples published a research about a mold (Penicillium) ina water well that had an antibacterial action.[19][20]

Ernest Duchesne documented it in an 1897 paper, which was not accepted by the Institut Pasteur because of hisyouth. In March 2000, doctors at the San Juan de Dios Hospital in San José, Costa Rica, published the manuscriptsof the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight (1887–1944). They reportedPicado's observations on the inhibitory actions of fungi of the genus Penicillium between 1915 and 1927. Picadoreported his discovery to the Paris Academy of Sciences, yet did not patent it, even though his investigations startedyears before Fleming's. Joseph Lister was experimenting with Penicillum in 1871 for his aseptic surgery. He foundthat it weakened the microbes, but then he dismissed the fungi.These early investigations did not lead to the use of antibiotics to treat infection because they took place in obscurecircumstances, and the idea that infections were caused by transmissible agents was not widely accepted at the time.Sterilization measures had been shown to limit the outbreak and spread of disease; however, the mechanism oftransmission of disease by parasites, bacteria, viruses and other agents was unknown. In the late 19th century,knowledge was increasing of the mechanisms by which living organisms become infected, how they manageinfection once it has begun and, most importantly in the case of penicillin, the effect that natural and man-madeagents could have on the progress of infection.Fleming recounted that the date of his discovery of penicillin was on the morning of Friday, September 28, 1928.[21]

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 mistakenly left open, was contaminated by blue-green mould, which formed a visible growth. There was a halo of inhibited bacterial growth

Penicillin 6

around the mould. Fleming concluded the mould released a substance that repressed the growth and lysing thebacteria. He grew a pure culture and discovered 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 cultureof the Penicillium mould. Even in these early stages, penicillin was found to be most effective against Gram-positivebacteria, and ineffective against Gram-negative organisms and fungi. He expressed initial optimism that penicillinwould be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, andnoted its laboratory value in the isolation of Bacillus influenzae (now Haemophilus influenzae).[22] After furtherexperiments, Fleming was convinced penicillin could not last long enough in the human body to kill pathogenicbacteria, and stopped studying it after 1931. He restarted clinical trials in 1934, and continued to try to get someoneto purify it until 1940.[23]

Medical application

Florey (pictured), Fleming and Chainshared a Nobel Prize in 1945 for their

work on penicillin.

In 1930, Cecil George Paine, a pathologist at the Royal Infirmary inSheffield, attempted to use penicillin to treat sycosis barbae, eruptions inbeard follicles, but was unsuccessful, probably because the drug did notpenetrate the skin deeply enough. Moving on to ophthalmia neonatorum, agonococcal infection in infants, he achieved the first recorded cure withpenicillin, on November 25, 1930. He then cured four additional patients (oneadult and three infants) of eye infections, and failed to cure a fifth.[24]

In 1939, Australian scientist Howard Florey (later Baron Florey) and a teamof researchers (Ernst Boris Chain, Arthur Duncan Gardner, Norman Heatley,M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School ofPathology, University of Oxford made significant progress in showing the invivo bactericidal action of penicillin. Their attempts to treat humans failedbecause of insufficient volumes of penicillin (the first patient treated wasReserve Constable Albert Alexander), but they proved it harmless andeffective on mice.[25]

Some of the pioneering trials of penicillin took place at the RadcliffeInfirmary 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.[24] On March 14, 1942, John Bumstead and Orvan Hess saved a dyingpatient's life using penicillin.[26][27]

Mass productionThe chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in 1945.[28] Penicillin has sincebecome the most widely used antibiotic to date, and is still used for many Gram-positive bacterial infections. A teamof Oxford research scientists led by Australian Howard Florey and including Ernst Boris Chain and Norman Heatleydevised a method of mass-producing the drug. Florey and Chain shared the 1945 Nobel Prize in Medicine withFleming for their work. After World War II, Australia was the first country to make the drug available for civilianuse. Chemist John C. Sheehan at MIT completed the first total synthesis of penicillin and some of its analogs in theearly 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 US-made penicillin produced by Merck & Co.[29] Half of the total supply produced at the time was used on that one patient. By June 1942, just enough US penicillin was available to treat ten patients.[30]

In July 1943, the War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops

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fighting in Europe.[31] A mouldy cantaloupe in a Peoria, Illinois, market in 1943 was found to contain the best andhighest-quality penicillin after a worldwide search.[32] The discovery of the cantaloupe, and the results offermentation research on corn steep liquor at the Northern Regional Research Laboratory at Peoria, Illinois, allowedthe 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 MargaretHutchinson Rousseau.[33] As a direct result of the war and the War Production Board, by June 1945, over 646 billionunits per year were being produced.[31]

Penicillin was being mass-produced in 1944.

G. Raymond Rettew made a significantcontribution to the American war effort byhis techniques to produce commercialquantities of penicillin.[34] During WorldWar II, penicillin made a major difference inthe number of deaths and amputationscaused by infected wounds among Alliedforces, saving an estimated 12%–15% oflives. Availability was severely limited,however, by the difficulty of manufacturinglarge quantities of penicillin and by therapid renal clearance of the drug,necessitating frequent dosing. Penicillin isactively excreted, and about 80% of apenicillin dose is cleared from the bodywithin three to four hours of administration.Indeed, during the early penicillin era, thedrug was so scarce and so highly valued that it became common to collect the urine from patients being treated, sothat the penicillin in the urine could be isolated and reused.[35] This was not a satisfactory solution, so researcherslooked for a way to slow penicillin excretion. They hoped to find a molecule that could compete with penicillin forthe organic acid transporter responsible for excretion, such that the transporter would preferentially excrete thecompeting 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 ofpenicillin, increasing penicillin's concentration and prolonging its activity. Eventually, the advent of mass-productiontechniques and semi-synthetic penicillins resolved the supply issues, so this use of probenecid declined.[35]

Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.[4]

Unethical experimentationIn a 1946 to 1948 study in Guatemala, U.S. researchers used prostitutes to infect prison inmates, insane asylumpatients, and Guatemalan soldiers with syphilis and other sexually transmitted diseases (STDs), to test theeffectiveness of penicillin in treating such diseases. They later tried infecting people with "direct inoculations madefrom syphilis bacteria poured into the men's penises and on forearms and faces that were slightly abraded ... or in afew cases through spinal punctures".[36] Approximately 1300 people were infected as part of the study (includingorphaned children). The study was sponsored by the Public Health Service, the National Institutes of Health and thePan American Health Sanitary Bureau (now the World Health Organization's Pan American Health Organization)and the Guatemalan government. The team was led by John Charles Cutler, who later participated in the Tuskegeesyphilis experiments. Cutler chose to do the study in Guatemala because he would not have been permitted to do it inthe United States.[37][38][39][40] The Presidential Commission for the Study of Bioethical Issues determined that 83people died; however, it was not possible to determine whether the experiments were the direct cause of death.[41]

Penicillin 8

Developments from penicillinThe narrow range of treatable diseases or "spectrum of activity" of the penicillins, along with the poor activity of theorally active phenoxymethylpenicillin, led to the search for derivatives of penicillin that could treat a wider range ofinfections. 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 originalpenicillins. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin, dicloxacillin, andmethicillin. These were significant for their activity against β-lactamase-producing bacterial species, but wereineffective against the methicillin-resistant Staphylococcus aureus (MRSA) 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 theβ-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most important, thecephalosporins, still retain it at the center of their structures.[42]

References[1] " penicillin (http:/ / web. archive. org/ web/ 20090616022448/ http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split. jsp?pg=/

ppdocs/ us/ common/ dorlands/ dorland/ six/ 000079881. htm)" at Dorland's Medical Dictionary[2] Garrod, L. P. (1960). "Relative Antibacterial Activity of Three Penicillins". British Medical Journal 1 (5172): 527–29.

doi:10.1136/bmj.1.5172.527.[3] Garrod, L. P. (1960). "The Relative Antibacterial Activity of Four Penicillins". British Medical Journal 2 (5214): 1695–6.

doi:10.1136/bmj.2.5214.1695. PMC 2098302. PMID 13703756.[4] Rossi S, editor, ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook. ISBN 0-9757919-2-3.[5] Kasten, Britta; Reski, Ralf (30 March 1997). "β-lactam antibiotics inhibit chloroplast division in a moss (Physcomitrella patens) but not in

tomato (Lycopersicon esculentum)" (http:/ / cat. inist. fr/ ?aModele=afficheN& cpsidt=2640663). Journal of Plant Physiology 150 (1–2):137–140. doi:10.1016/S0176-1617(97)80193-9. .

[6] learnchem.net Stoichiometry (http:/ / www. learnchem. net/ tutorials/ stoich. shtml) Section: Percent Mass. By Takalah. Retrieved on Jan 9,2009

[7] Drug Safety > Penicillin G (http:/ / drugsafetysite. com/ penicillin-g-benzathine/ ) Retrieved on Jan 9, 2009[8] SymplusWiki > penicillin G (http:/ / www. symplus. com/ legacy/ biowiki/ en/ penicillin) Retrieved on Jan 9, 2009[9] Barbosa S., Taboada P., Ruso J.M., Attwood D., Mosquera V. (August 2003). "Complexes of penicillins and human serum albumin studied

by static light scattering". Colloids and Surfaces A: Physicochemical and Engineering Aspects 224 (1–3): 251–6.doi:10.1016/S0927-7757(03)00322-4.

[10] Al-Abdallah, Q., Brakhage, A. A., Gehrke, A., Plattner, H., Sprote, P., Tuncher, A. (2004). "Regulation of Penicillin Biosynthesis inFilamentous Fungi". In Brakhage AA. Molecular Biotechnolgy of Fungal beta-Lactam Antibiotics and Related Peptide Synthetases.pp. 45–90. doi:10.1007/b99257. ISBN 3-540-22032-1.

[11] Brakhage, A. A. (1998). "Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi" (http:/ / mmbr. asm. org/ cgi/ content/short/ 62/ 3/ 547). Microbiol Mol Biol Rev. 62 (3): 547–85. PMC 98925. PMID 9729600. .

[12] Baldwin, J. E., Byford, M. F., Clifton, I., Hajdu, J., Hensgens, C., Roach, P, Schofield, C. J. (1997). "Proteins of the Penicillin BiosynthesisPathway". Curr Opin Struct Biol. (7): 857–64.

[13] Fernandez, F. J., Fierro, F., Gutierrez, S, Kosalkova, K . Marcos, A. T., Martin, J. F., Velasco, J. (September 1994). "Expression of Genesand Processing of Enzymes for the Biosynthesis of Penicillins and Cephalosporms". Anton Van Lee 65 (3): 227–43. doi:10.1007/BF00871951.PMID 7847890.

[14][14] Baker, W. L., Lonergan, G. T. "Chemistry of Some Fluorescamine-Amine Derivatives with Relevance to the Biosynthesis ofBenzylpenicillin by Fermentation". J Chem Technol Biot. 2002, 77, pp1283-1288.

[15] "Alexander Fleming – Time 100 People of the Century" (http:/ / 205. 188. 238. 181/ time/ time100/ scientist/ profile/ fleming. html). Time. ."It was a discovery that would change the course of history. The active ingredient in that mold, which Fleming named penicillin, turned out tobe an infection-fighting agent of enormous potency. When it was finally recognized for what it is — the most efficacious life-saving drug inthe world — penicillin would alter forever the treatment of bacterial infections."

[16] Houbraken J, Frisvad JC, Samson RA (2011) Fleming's penicillin producing strain is not Penicillium chrysogenum but P. rubens. IMAFungus 2(1):87-95

[17] Phil. Trans., 1876, 166, pp27-74. Referred to at: Discoveries of anti-bacterial effects of penicillium moulds before Fleming[18] J.M. Caminhoá, 'Cogumélos uteis, nocivos e curiosos.' In: “Elementos de Botânica geral e médica”, 1877, p1718. Published in 5 vols,

Typographia Nacional, Rio de Janeiro, Brazil. (Reported by Prof P.R. Chocair as held at the Biblioteca da Câmara Municipal de São Paulo,Brasil)

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[19] http:/ / www. almanacco. rm. cnr. it/ reader/ cw_usr_view_recensione?id_articolo=1704& giornale=1679[20] http:/ / festival2011. festivalscienza. it/ site/ home/ programma-2011/ eventi-per-tipo/ conferenze/

vincenzo-tiberio-vero-scopritore-degli-antibiotici. html[21] Haven, Kendall F. (1994). Marvels of Science : 50 Fascinating 5-Minute Reads. Littleton, Colo: Libraries Unlimited. pp. 182.

ISBN 1-56308-159-8.[22] Fleming A. (1929). "On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B.

influenzæ". Br J Exp Pathol 10 (31): 226–36.[23] Brown, Kevin. (2004). Penicillin Man: Alexander Fleming and the Antibiotic Revolution.. Stroud: Sutton. ISBN 0-7509-3152-3.[24] Wainwright M, Swan HT (January 1986). "C.G. Paine and the earliest surviving clinical records of penicillin therapy". Medical History 30

(1): 42–56. PMC 1139580. PMID 3511336.[25] Drews, Jürgen (March 2000). "Drug Discovery: A Historical Perspective". Science 287 (5460): 1960–4. doi:10.1126/science.287.5460.1960.

PMID 10720314.[26] Saxon, W. (June 9, 1999). "Anne Miller, 90, first patient who was saved by penicillin" (http:/ / www. nytimes. com/ 1999/ 06/ 09/ us/

anne-miller-90-first-patient-who-was-saved-by-penicillin. html). The New York Times. .[27] Krauss K, editor (1999). "Yale-New Haven Hospital Annual Report" (http:/ / www. ynhh. org/ general/ annreport/ ynhh99ar. pdf) (PDF).

New Haven: Yale-New Haven Hospital. .[28] The Nobel Prize in Chemistry 1964, Perspectives (http:/ / www. nobelprize. org/ nobel_prizes/ chemistry/ laureates/ 1964/ perspectives.

html). Retrieved 14 July 2012.[29] The First Use of Penicillin in the United States (http:/ / www. annals. org/ cgi/ content/ full/ 149/ 2/ 135), by Charles M. Grossman. Annals

of Internal Medicine 15 July 2008: Volume 149, Issue 2, Pages 135-136.[30] John S. Mailer, Jr., and Barbara Mason. "Penicillin : Medicine's Wartime Wonder Drug and Its Production at Peoria, Illinois" (http:/ / www.

lib. niu. edu/ ipo/ 2001/ iht810139. html). lib.niu.edu. . Retrieved 2008-02-11.[31] John Parascandola (1980). The History of antibiotics: a symposium. American Institute of the History of Pharmacy No. 5.

ISBN 0-931292-08-5.[32] Mary Bellis. "The History of Penicillin" (http:/ / inventors. about. com/ od/ pstartinventions/ a/ Penicillin. htm). Inventors. About.com. .

Retrieved 2007-10-30.[33] Chemical Heritage (http:/ / www. chemheritage. org/ women_chemistry/ med/ rousseau. html) Manufacturing a Cure: Mass Producing

Penicillin[34] "ExplorePAhistory.com" (http:/ / explorepahistory. com/ hmarker. php?markerId=974). . Retrieved 2009-05-11.[35] Silverthorn, DU. (2004). Human physiology: an integrated approach. (3rd ed.). Upper Saddle River (NJ): Pearson Education.

ISBN 0-8053-5957-5.[36] Michael Cook (02 Oct 2010). "US apologizes for 1940s unethical research in Guatemala" (http:/ / www. bioedge. org/ index. php/ bioethics/

bioethics_article/ 9236). BioEdge. .[37] "U.S. sorry for Guatemala syphilis experiment" (http:/ / www. cbc. ca/ health/ story/ 2010/ 10/ 01/ syphilis-guatemala. html). CBC News.

October 1, 2010. .[38] Rob Stein (October 1, 2010). "U.S. apologizes for newly revealed syphilis experiments done in Guatemala" (http:/ / www. washingtonpost.

com/ wp-dyn/ content/ article/ 2010/ 10/ 01/ AR2010100104457. html?hpid=topnews). Washington Post. .[39] "US sorry over deliberate sex infections in Guatemala" (http:/ / www. bbc. co. uk/ news/ world-us-canada-11454789). BBC News. October

1, 2010. .[40] Chris McGreal (October 1, 2010). "US says sorry for 'outrageous and abhorrent' Guatemalan syphilis tests" (http:/ / www. guardian. co. uk/

world/ 2010/ oct/ 01/ us-apology-guatemala-syphilis-tests). Guardian (London). .[41] Rob Stein (August 30, 2011). "U.S. scientists knew 1940s Guatemalan STD studies were unethical, panel finds" (http:/ / www.

washingtonpost. com/ national/ health-science/ us-scientists-knew-1940s-guatemalan-std-studies-were-unethical-panel-finds/ 2011/ 08/ 26/gIQA2CxLoJ_story. html). Washington Post (?). .

[42] James, PharmD, Christopher W.; Cheryle Gurk-Turner, RPh (2001 January). "Cross-reactivity of beta-lactam antibiotics". Baylor UniversityMedical Center Proceedings (Dallas, Texas: Baylor University Medical Center) 14 (1): 106–7. PMC 1291320. PMID 16369597.

External links• Model of Structure of Penicillin, by Dorothy Hodgkin et al., Museum of the History of Science, Oxford (http:/ /

users. ox. ac. uk/ ~jesu1458/ )• 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.(http:/ / www. youtube. com/ watch?v=7qeZLLhx5kU)

• Penicillin Released to Civilians Will Cost $35 Per Patient (http:/ / books. google. com/

books?id=PN8DAAAAMBAJ& pg=PA47& dq=popular+ science+ antitank+ 1941& hl=en&

ei=ZIiZTObfGcufnAe9kdWsDw& sa=X& oi=book_result& ct=result& resnum=7&

Penicillin 10

ved=0CEAQ6AEwBjgK#v=onepage& q& f=true) August 1944 article at bottom of page

Article Sources and Contributors 11

Article Sources and ContributorsPenicillin  Source: http://en.wikipedia.org/w/index.php?oldid=503671053  Contributors: 0x6D667061, 1exec1, 2004-12-29T22:45Z, 25or6to4, A-izzle, A876, A8UDI, APLAdam, ASarnat,AThing, AaronTownsend, Abeg92, Abulmagd, Acather96, Adashiel, Addshore, AdjustShift, Adrian J. Hunter, Adventure8410, AgentLewis, Aidan Croft, Aitias, Alan Liefting, Alansohn, Alant,Alecwh, Alex.tan, Alexandria, Alfie66, Alias Flood, Alienbrett, Allens, AlphaEta, Alsandro, AmyzzXX, Andonic, Andre Engels, Andres, Andyras, Angel caboodle, Animum, Anna Frodesiak,Antandrus, Antiuser, Ar-wiki, Arcadian, ArglebargleIV, ArielGold, Arnaugir, Arpan1234, Arthena, Ashujo, AuburnPilot, Auntof6, AxelBoldt, Backslash Forwardslash, Batchelor, Beefball,Beeline23, Beetstra, Ben-Zin, Benlisquare, Bentogoa, Bernarddb, Biggy123456, Bignoter, Bigtam01, Bigwyrm, Biiru, Billybob73, Bissinger, Bkell, Blacknproud92, Blaxthos, BlueAmethyst,Bluedenmark, Bluerasberry, Bobjack13, Bobo192, Bobthebuilder127, Boing! said Zebedee, Bovineone, Bparadisin, Brandon, Brutaldeluxe, Bryan Derksen, Bucketsofg, Bunchofgrapes,Bwilkins, CJLL Wright, Cactus.man, Cacycle, Caillan, Caledones, Camp3rstrik3r, CanadianLinuxUser, Canek, CanisRufus, Captain panda, CardinalDan, Cardsplayer4life, Carinemily,Carstensen, Catgut, Cdecoro, Celiaaymerich, Cenarium, Ceyockey, Chemical Engineer, Chepe, Christian List, Christopher Parham, Cinik, Citicat, Clarince63, Clawson, Clemux, Closedmouth,Cometstyles, Conversion script, CopperSquare, Courcelles, Coviepresb1647, Cpl Syx, CrazyChemGuy, CrookedAsterisk, Cruccone, Cst17, Cybercobra, Cyrus XIII, DMacks, DO11.10, DVD RW, DWeir, Da5id403, Damieng, Damuna, Dan D. Ric, Daniel Olsen, DanielDemaret, Dave6, David.Mestel, DavidJ710, Davidruben, Dbrear, DeadEyeArrow, Debresser, December12AC, Deego,Delldot, Delta G, DerHexer, Devchemistrynmr, Deviator13, Dfgrthrt, Dgw, Diannaa, Discospinster, Dissolve, Dl573, Dlohcierekim's sock, Dmross41, Doberman Pharaoh, Dodo19, Dominik92,Dominus, Donfbreed, Dougofborg, Doulos Christos, Download, Dpm, Dr.Kerr, DrMicro, DragonflySixtyseven, Dragonslayer2065, Drphilharmonic, Dub8lad1, Ducknish, Durova, Dyfrgi,Dyslexic3, DéRahier, E Wing, E2e3v6, Edgar181, Egghead06, Ejcvmd, El3ctr0nika, ElBenevolente, Elena the Quiet, Emarsee, Emiao, Epbr123, Erc, Erianna, Erich gasboy, Ericoides, Ettrig,Evan G, Ewen, Excirial, Exert, Ezhuttukari, FF2010, FLip x Trickz, FQuist, Fabullus, Falcon8765, Faradayplank, Fatmandead, Favonian, Feinoha, Feldmarshal, FetchcommsAWB,Fieldday-sunday, Fight Da Powa, Firehawk, FitzColinGerald, Fleminra, Flockmeal, Flowerpotman, Flydpnkrtn, Footwarrior, Fraslet, Fredrik, Free Bear, Frencheigh, FreplySpang, Fuzzygerdes,Fvasconcellos, Fvw, G3pro, GDonato, Gaius Cornelius, Gak, Gbleem, Gderbysh, George The Dragon, Gigemag76, Ginkgo100, Glacialfox, Glen, Gnarky, Goatlunch, Gogo Dodo, Gonzofan2007, Gpans, Graham87, Gravitan, Greenman, Group29, Guitare madness, Hallows AG, Hannah94018, Hardyplants, Hausjellp, Heracles31, Heron, Hertz1888, Hga, Hobartimus, HomerLandskirty, Hoo man, Howdoesthiswo, IRP, Iain southern, Iamunknown, Icairns, Iced Kola, Icseaturtles, Ideal gas equation, Ijustam, Impala2009, Infocidal, Iorsh, Iridescent, IrishPete,IronGargoyle, Ixfd64, J'raxis, J-stan, J.delanoy, JCRules, JForget, Ja 62, Jackehammond, Jackwe, Jakob Theorell, James1234b, JamesBWatson, Jatlas, Jauerback, Jaxsonjo, JayC, Jcspurrell,Jdforrester, JdwNYC, Jeff G., Jeffrey Mall, Jewk, Jfdwolff, Jh12, Jmak, Jmcc150, Jmh649, Joeylawn, John254, Johnleemk, Johntch497, Jon186, Jonathanstray, Jonpawlik, JoshLMeyer,Joshloves, Joyous!, Jrcash, Jrkarp, Jrugordon, Julesd, Jusdafax, KConWiki, KGasso, KaiTheL, Kakerlakk13, Karl-Henner, Katfish, Kazvorpal, Keenan Pepper, Keeperoftheforest, Kei Jo, KeithD, Kelly Martin, Kf4bdy, Khoikhoi, Khsuan, Kizor, Kkp225, Kmg90, KnowledgeOfSelf, Kralizec!, Krich, Kristen Eriksen, Krystaltia, Ks0stm, Kukini, Kurrupt3d, Kuru, Kusername, Kvn8907, LKensington, L33th4x0rguy, Latka, Leafyplant, Leandrod, LeaveSleaves, LedgendGamer, Letatcestmoi94, Lhynard, Lightenoughtotravel, Lights, LittleDan, Localh77, Lord of the Pit,Loren.wilton, LowLifer, Luna Santin, M1ss1ontomars2k4, MJBurrage, MPerel, Macaddct1984, Mad Max, Madang1965, Magnus Manske, Mais oui!, Mallocks, Mandsford, ManiF, Marc Venot,Marek69, Maria Sieglinda von Nudeldorf, Martin451, Martynas Patasius, MastCell, Matiz991991, Matt Deres, Mattg82, Matthewrbowker, Mav, Max Rex, Maxim Razin, Mayooranathan, Mazca,McSly, Mcorazao, Mcstrother, Mdw0, Medos2, Melvalevis, Micahownz, Michael Devore, Michael Hardy, MightyWarrior, Mijobe, Mikael Häggström, Mike Rosoft, Mike2vil, MikeGinnyMD,MikeLeeds, Mikeo, Minimcnoon, Miniyazz, Miquonranger03, Misza13, MithrandirAgain, Mjw1904, Mlpearc, Modeha, Monkeypd, Mononomic, Montana's Defender, Montgomery '39, MrBungle, Msikma, Mstroeck, Mushin, MusicTree3, Mutants11, Mycomp, Mysid, N5iln, Nakon, Nathanjp, NawlinWiki, NaySay, Necro280, Ned Scott, Neilymon, NellieBly, Nemetona, Neoprote,NewEnglandYankee, NickCT, Ninja12345, NinjaLore, Nishkid64, Nivix, Noctibus, Noisy, NrDg, Nunh-huh, Nuttycoconut, O, Oda Mari, Odie5533, Oerdnj, Ohnoitsjamie, Old Moonraker, Oncop53, Oneiros, Opelio, Orbitalwow, OverlordQ, OwenBlacker, Oxguy3, Oxymoron83, Para, Paul D. Anderson, Paul Erik, Paul McMahon, Pearcef09, Pedantic of Purley, Pedro999999999, PersianPoet Gal, Peter rowan, Pfalstad, Pharaoh of the Wizards, Philip Trueman, Philippe, Phthoggos, Piledhigheranddeeper, Pill, Pinethicket, Pingveno, PitrPatr, Pne, Pointednose, Pope Tetsuo,Postglock, Prari, Primacag, PuzzletChung, Pyropenta, Quadell, Quinxorin, QuiteUnusual, Qxz, RDBrown, RSoper, RXPhd, Ramsis II, Randi-Gordan-did-it, Raven4x4x, RayJohnstone, Rdrgz93,Reach Out to the Truth, Reaper Eternal, RedSpruce, ReinforcedReinforcements, RelentlessRecusant, RexNL, Rfl, Rich Farmbrough, Richard Arthur Norton (1958- ), Rifleman 82, Rjwilmsi,Roadrunner, Robbolt, Robert Merkel, RobertG, Robinrocks, Robma, Rose1015, RoyBoy, Rsrikanth05, Rumping, Russoc4, Ryan Vesey, Ryman1994, Ryoga Godai, S2000magician,SHIMONSHA, Sabedon, Sabisteb, Saif2saif, Salvadorjo, Sasata, Savorie, ScAvenger, Scholariusx, Schzmo, Scotty134, Sean D Martin, Sellyme, Senseiwa, Seuraza, Shanes, Shirulashem,Shniken1, Shoy, Sjakkalle, Skajaboo, Slightsmile, Sligocki, Smalljim, Smashville, Smokefoot, Smyth, Socialservice, Soliloquial, Soundoftoday, Spencer, Spiral5800, Spiraling, Srose, Star-lists,Startstop123, Stepa, Stephenb, Steve, Steve98052, Stonysleep, Sunny yang, Superdude43097, Supermarwa2, Svanslyck, Svetovid, Swesty1, Syd Midnight, SystemBuilder, Szwejk, TDN169,THEN WHO WAS PHONE?, Tannkremen, Tanty, Tarquin, Tartan, Techelf, Tempshill, Tenzerothree, Terrace4, The Cunctator, The Letter J, The Thing That Should Not Be, TheEgyptian,Theda, Three-quarter-ten, Threemadness, Tide rolls, Tiptoety, Titoxd, Tobby72, Toddst1, Tomas.malinauskas, Tonusperegrinus, Town of Cats, Transformasian, Trishfish73, Trusilver, Tsemii,Uncle Dick, UpstateNYer, Uthbrian, Vector2, VigilancePrime, Vincenzo2k7, Vishnava, Vl'hurg, WDavis1911, WQDW412, Ward3001, Wasell, Wavelength, Wayward, Wentao1Hao,West.andrew.g, WhaleyTim, WhisperToMe, Whywhenwhohow, Wikieditor06, Wikipelli, Wildthing61476, Will Beback, Willking1979, Wimt, Wingman4l7, Wknight94, Wolfkeeper, Wolftengu,Yachtsman1, Yamamoto Ichiro, Ybbor, Yerbamate, Yerpo, Yikrazuul, Yonatan, YourFEAR, Yourboyog, Ytcracker, Zandperl, Zeamays, Ziva David, Zoga50, 1490 ,ساجد امجد ساجد anonymousedits

Image Sources, Licenses and ContributorsImage:Penicillin core.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Penicillin_core.svg  License: Public Domain  Contributors: YikrazuulFile:Penicillin inhibition.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Penicillin_inhibition.svg  License: Creative Commons Attribution 3.0  Contributors: McstrotherFile:Penicillin spheroplast generation.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Penicillin_spheroplast_generation.svg  License: Creative Commons Attribution 3.0 Contributors: McstrotherFile:Penicillin-G 3D.png  Source: http://en.wikipedia.org/w/index.php?title=File:Penicillin-G_3D.png  License: Public Domain  Contributors: CacycleImage:Penicillin-nucleus-3D-balls.png  Source: http://en.wikipedia.org/w/index.php?title=File:Penicillin-nucleus-3D-balls.png  License: Public Domain  Contributors: Benjah-bmm27Image:Penicillin-biosynthesis.png  Source: http://en.wikipedia.org/w/index.php?title=File:Penicillin-biosynthesis.png  License: Creative Commons Attribution-ShareAlike 3.0 Unported Contributors: CacycleFile:Howard Walter Florey 1945.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Howard_Walter_Florey_1945.jpg  License: Public Domain  Contributors: Nobel FoundationImage:PenicillinPSAedit.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:PenicillinPSAedit.jpg  License: Public Domain  Contributors: Common Good, Fran McCrory, Hohum,Tryphon, 1 anonymous edits

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