Discovery of penicillin

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Sample of penicillin mould presented by Alexander Fleming to Douglas Macleod in 1935 Sample of penicillin mould presented by Alexander Fleming to Douglas Macleod, 1935 (9672239344).jpg
Sample of penicillin mould presented by Alexander Fleming to Douglas Macleod in 1935

Ancient societies used moulds to treat infections, and in the following centuries many people observed the inhibition of bacterial growth by moulds. While working at St Mary's Hospital in London in 1928, Scottish physician Alexander Fleming was the first to experimentally determine that a Penicillium mould secretes an antibacterial substance, which he named "penicillin". The mould was found to be a variant of Penicillium notatum (now called Penicillium rubens ), a contaminant of a bacterial culture in his laboratory. The work on penicillin at St Mary's ended in 1929.

Contents

In 1939, a team of scientists at the Sir William Dunn School of Pathology at the University of Oxford, led by Howard Florey that included Edward Abraham, Ernst Chain, Norman Heatley and Margaret Jennings, began researching penicillin. They developed a method for cultivating the mould, and extracting, purifying and storing penicillin from it. They created an assay for measuring its purity. They carried out experiments with animals to determine penicillin's safety and effectiveness before conducting clinical trials and field tests. They derived its chemical formula and determined how it works. The private sector and the United States Department of Agriculture located and produced new strains and developed mass production techniques. Penicillin became an important part of the Allied war effort in the Second World War, saving the lives of thousands of soldiers. Fleming, Florey and Chain shared the 1945 Nobel Prize in Physiology or Medicine for its discovery and development.

Background

Many ancient cultures, including those in Australia, China, Egypt, Greece and India, independently discovered the useful properties of fungi and plants in treating infection. These treatments often worked because many organisms, including many species of mould, naturally produce antibiotic substances. However, ancient practitioners could not precisely identify or isolate the active components in these organisms. [1] [2]

Alexander Fleming in his laboratory at St Mary's Hospital, London Synthetic Production of Penicillin TR1468.jpg
Alexander Fleming in his laboratory at St Mary's Hospital, London

While working at St Mary's Hospital, London, in 1928, a Scottish physician, Alexander Fleming, was investigating the pattern of variation in S. aureus. [3] He was inspired by the discovery of an Irish physician, Joseph Warwick Bigger, and his two students, C.R. Boland and R.A.Q. O’Meara, at Trinity College, Dublin, in 1927. Bigger and his students found that when they cultured a particular strain of S. aureus, which they had designated "Y" and isolated a year earlier from the pus of a patient's axillary abscess, the bacterium grew into a variety of strains. They published their discovery as "Variant colonies of Staphylococcus aureus" in The Journal of Pathology and Bacteriology, concluding:

We were surprised and rather disturbed to find, on a number of plates, various types of colonies which differed completely from the typical aureus colony. Some of these were quite white; some, either white or of the usual colour were rough on the surface and with crenated margins. [4] : 261 

Fleming and his research scholar Daniel Merlin Pryce pursued this experiment but Pryce was transferred to another laboratory in early 1928. After a few months of working alone, a new scholar, Stuart Craddock, joined Fleming. Their experiment was successful and Fleming was planning and agreed to write a report in A System of Bacteriology to be published by the Medical Research Council (MRC) by the end of 1928. [3] In August, Fleming spent the summer break with his family at his country home The Dhoon at Barton Mills, Suffolk. Before leaving his laboratory, he inoculated several culture plates with S. aureus. He kept the plates aside on one corner of the table away from direct sunlight and to make space for Craddock to work in his absence. While on vacation, he was appointed Professor of Bacteriology at the St Mary's Hospital Medical School on 1 September 1928. He arrived at his laboratory on 3 September, where Pryce was waiting to greet him. [5] As he and Pryce examined the culture plates, they found one with an open lid and the culture contaminated with a blue-green mould. In the contaminated plate the bacteria around the mould did not grow, while those farther away grew normally, meaning that the mould killed the bacteria. [6] Fleming commented as he watched the plate: "That's funny". [5] [6] Pryce remarked to Fleming: "That's how you discovered lysozyme." [7] Fleming photographed the culture and took a sample of the mould for identification before preserving the culture with formaldehyde. [8]

St Mary's Hospital showing Fleming's lab and Praed Street Flemming laboratory (3).JPG
St Mary's Hospital showing Fleming's lab and Praed Street

Fleming resumed his vacation and returned in September. [3] According to his notes on 30 October, [8] he collected the original mould and grew it in culture plates. After four days he found that the plates developed large colonies of the mould. He repeated the experiment with the same bacteria-killing results. He later recounted his experience:

When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionize all medicine by discovering the world's first antibiotic, or bacteria killer. But I suppose that was exactly what I did. [9]

He concluded that the mould was releasing a substance that was inhibiting bacterial growth, and he produced culture broth of the mould and subsequently concentrated the antibacterial component. [10] After testing against different bacteria, he found that the mould could kill only specific, Gram-positive bacteria. [11] For example, staphylococcus, streptococcus , and diphtheria bacillus ( Corynebacterium diphtheriae ) were easily killed; but there was no effect on typhoid bacterium ( Salmonella typhimurium ) and a bacterium once thought to cause influenza ( Haemophilus influenzae ). He prepared a large-culture method from which he could obtain large amounts of the mould juice. He called this juice "penicillin", explaining the reason as "to avoid the repetition of the rather cumbersome phrase 'Mould broth filtrate'." [12] He invented the name on 7 March 1929. [5] In his Nobel lecture he gave a further explanation, saying:

I have been frequently asked why I invented the name "Penicillin". I simply followed perfectly orthodox lines and coined a word which explained that the substance penicillin was derived from a plant of the genus Penicillium just as many years ago the word "Digitalin" was invented for a substance derived from the plant Digitalis . [13]

For the effect on the cultures of staphylococci that Fleming observed, the mould had to be growing before the bacteria began to grow, because penicillin is only effective on bacteria when they are reproducing. Fortuitously, the temperature in the laboratory during that August was optimum first for the growth of the mould, below 20 °C (68 °F), and later in the month for the bacteria, when it reached 25 °C (77 °F). Had Fleming not left the cultures on his laboratory bench and put them in an incubator, the phenomenon would not have occurred. [14]

Fleming had no training in chemistry; he left all the chemical work to Craddock, once remarking "I am a bacteriologist, not a chemist." [3] In January 1929, he recruited Frederick Ridley, his former research scholar who had studied biochemistry, specifically to the study the chemical properties of the mould. [6] But they could not isolate penicillin, and before the experiments were over, Craddock and Ridley both left Fleming for other jobs. It was due to his failure to isolate the compound that Fleming practically abandoned further research on the chemical aspects of penicillin. [5]

Identification of the mould

After structural comparison with different species of Penicillium, Fleming initially believed that his specimen was Penicillium chrysogenum, a species described by an American microbiologist Charles Thom in 1910. He was fortunate that Charles John Patrick La Touche, an Irish botanist, had just recently joined St Mary's as a mycologist to investigate fungi as the cause of asthma. La Touche identified the specimen as Penicillium rubrum, the identification used by Fleming in his publication. [15] [16]

In 1931, Thom re-examined different Penicillium including that of Fleming's specimen. He came to a confusing conclusion, stating, "Ad. 35 [Fleming's specimen] is P. notatum WESTLING. This is a member of the P. chrysogenum series with smaller conidia than P. chrysogenum itself." [17] From then on, Fleming's mould was synonymously referred to as P. notatum and P. chrysogenum. But Thom adopted and popularised the use of P. chrysogenum. [18] In addition to P. notatum, newly discovered species such as P. meleagrinum and P. cyaneofulvum were recognised as members of P. chrysogenum in 1977. [19] To resolve the confusion, the Seventeenth International Botanical Congress held in Vienna, Austria, in 2005 formally adopted the name P. chrysogenum as the conserved name ( nomen conservandum). [20] Whole genome sequence and phylogenetic analysis in 2011 revealed that Fleming's mould belongs to P. rubens, a species described by Belgian microbiologist Philibert Biourge in 1923. [21] [22]

Fleming at work in his laboratory at St Mary's Hospital, London, during the Second World War Professor Alexander Fleming at work in his laboratory at St Mary's Hospital, London, during the Second World War. D17801.jpg
Fleming at work in his laboratory at St Mary's Hospital, London, during the Second World War

The source of the fungal contamination in Fleming's experiment remained a speculation for several decades. Fleming suggested in 1945 that the fungal spores came through the window facing Praed Street. This story was regarded as a fact and was popularised in literature, [23] starting with George Lacken's 1945 book The Story of Penicillin. [5] But it was later disputed by his co-workers including Pryce, who testified much later that Fleming's laboratory window was kept shut all the time. [24] Ronald Hare also agreed in 1970 that the window was most often locked because it was difficult to reach due to a large table with apparatuses placed in front of it. In 1966, La Touche told Hare that he had given Fleming thirteen specimens of fungi (ten from his lab) and only one from his lab was showing penicillin-like antibacterial activity. [23] After this, a consensus developed that Fleming's mould had come from La Touche's lab, a floor below Fleming's, as spores which had drifted in through the open doors. [25]

Craddock developed severe infection of the nasal antrum (sinusitis) and had undergone surgery. Fleming made use of the surgical opening of the nasal passage and started injecting penicillin on 9 January 1929 but without any effect, probably because the infection was with H. influenzae, a bacterium unsusceptible to penicillin. [23] Fleming gave some of his original penicillin samples to his colleague, surgeon Arthur Dickson Wright for clinical testing in 1928. [26] [27] Although Wright reportedly said that it "seemed to work satisfactorily," there are no records of its use. [28] In 1930 and 1931, Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, was the first to successfully use penicillin for medical treatment. [29] He attempted to treat sycosis (eruptions in beard follicles) with penicillin but was unsuccessful, probably because the drug did not penetrate deep enough into the skin. He cured three babies with ophthalmia neonatorum, an eye infection, and a local coal miner whose eye had become infected after an accident, but he did not publish his work. [30] [31]

Reception and publication

Fleming's discovery was initially regarded as unimportant. Even as he showed his culture plates to his colleagues, all he received was an indifferent response. He described the discovery on 13 February 1929 before the Medical Research Club. His presentation, titled "A medium for the isolation of Pfeiffer's bacillus", did not receive any particular attention. [3]

In 1929, Fleming reported his findings to the British Journal of Experimental Pathology on 10 May 1929, and published them in the next month's issue. [32] His article failed to attract any serious attention. Fleming himself was quite unsure of the medical application of his work and was more concerned with its the application for bacterial isolation, as he concluded:

In addition to its possible use in the treatment of bacterial infections, penicillin is certainly useful to the bacteriologist for its power of inhibiting unwanted microbes in bacterial cultures so that penicillin-insensitive bacteria can readily be isolated. A notable instance of this is the very easy isolation of Pfeiffer's bacillus of influenza when penicillin is used ... It is suggested that it may be an efficient antiseptic for application to, or injection into, areas infected with penicillin-sensitive microbes. [32]

G. E. Breen, a fellow member of the Chelsea Arts Club, once asked Fleming if he thought it would ever be possible to make practical use of penicillin. Fleming gazed vacantly for a moment and then replied, "I don't know. It's too unstable. It will have to be purified, and I can't do that by myself." [3] In 1941, the British Medical Journal reported that

The original colony of this mould, which proved to be Penicillium notatum, inhibited the growth of staphylococci in its vicinity, and fluid cultures of it contained a substance, since known as "penicillin", which was strongly inhibitory to the growth of various mainly Gram-positive bacteria. It came to be used at St. Mary's Hospital and elsewhere as an ingredient in selective culture media, and does not appear to have been considered as possibly useful from any other point of view. [33] [34]

Although Ridley and Craddock had demonstrated that penicillin was soluble in ether, acetone and alcohol as well as in water – information that would be critical to its isolation – Fleming erroneously claimed that it was soluble in alcohol and insoluble in ether and chloroform, which had not been tested. [35] In fact, penicillin is soluble in ethanol, ether and chloroform. [36]

Replication

In 1944, Margaret Jennings determined how penicillin acts, and showed that it has no lytic effects on mature organisms, including staphylococci; lysis occurs only if penicillin acts on bacteria during their initial stages of division and growth, when it interferes with the metabolic process that forms the cell wall. This brought Fleming's explanation into question, for the mould had to have been there before the staphylococci. Over the next twenty years, all attempts to replicate Fleming's results failed. In 1964, Ronald Hare took up the challenge. Like those before him, he found he could not get the mould to grow properly on a plate containing staphylococci colonies. He re-examined Fleming's paper and images of the original Petri dish. He attempted to replicate the original layout of the dish so there was a large space between the staphylococci. He was then able to get the mould to grow, but it had no effect on the bacteria. [37] [14]

Finally, on 1 August 1966, Hare was able to duplicate Fleming's results. However, when he tried again a fortnight later, the experiment failed. He considered whether the weather had anything to do with it, for Penicillium grows well in cold temperatures, but staphylococci do not. He conducted a series of experiments with the temperature carefully controlled, and found that penicillin would be reliably "rediscovered" when the temperature was below 20 °C (68 °F), but never when it was above 32 °C (90 °F). He consulted the weather records for 1928, and found that, as in 1966, there was a heat wave in mid-August followed by nine days of cold weather starting on 28 August that greatly favoured the growth of the mould. [37] [38] [14]

Nobel Prize

In 1939, ten years after work ceased at St. Mary's, a team of scientists at the Sir William Dunn School of Pathology at the University of Oxford, led by Howard Florey that included Edward Abraham, Ernst Chain, Norman Heatley and Margaret Jennings, began researching penicillin. [39] [40] Their starting point was Fleming's largely forgotten paper and a sample of penicillin mould Fleming had given to their laboratory in 1930. [41] [42] [43] They developed a method for cultivating the mould and extracting, purifying and storing penicillin from it, [44] [45] together with an assay for measuring its purity. [46] Chain hit upon the idea of freeze drying it, which enabled the water to be removed, resulting in a dry, brown powder. [44] [46] They carried out experiments with animals to determine penicillin's safety and effectiveness before conducting clinical trials and field tests. [47] [48] They derived its chemical structure and determined how it works. [37] [49] [50] The private sector and the United States Department of Agriculture located and produced new strains and developed mass production techniques. [51] [52] [53] During the Second World War penicillin became an important part of the Allied war effort, and is credited with saving the lives of thousands of soldiers. [54]

Nobel Prize in Physiology or Medicine medal awarded to Sir Alexander Fleming, on display at the National Museum of Scotland Nobel prize medal for medicine, Sweden, 1945, to Sir Alexander Fleming (1881-1955) who discovered Penicillin. On display at the National Museum of Scotland.jpg
Nobel Prize in Physiology or Medicine medal awarded to Sir Alexander Fleming, on display at the National Museum of Scotland

When the news of the curative properties of penicillin broke, Fleming revelled in the publicity. [55] [56] Journalists told a familiar story of a lone British scientist and a serendipitous discovery. The British medical historian Bill Bynum wrote:

The discovery and development of penicillin is an object lesson of modernity: the contrast between an alert individual (Fleming) making an isolated observation and the exploitation of the observation through teamwork and the scientific division of labour (Florey and his group). The discovery was old science, but the drug itself required new ways of doing science. [57]

In 1943, the Nobel committee received a single nomination for the Nobel Prize in Physiology or Medicine for Fleming and Florey from the British biochemist Rudolph Peters. The secretary of the Nobel committee, Göran Liljestrand, made an assessment of Fleming and Florey in the same year, but little was known about penicillin in Sweden at the time, and he concluded that more information was required. The following year, there was one nomination for Fleming alone and one for Fleming, Florey and Chain. Liljestrand and Nanna Svartz considered their work, and while both judged Fleming and Florey equally worthy of a Nobel Prize, the Nobel committee was divided, and decided to award the prize that year to Joseph Erlanger and Herbert S. Gasser instead. [58] [59]

In 1945 there were a large number of nominations for Florey and Fleming or both, and one for Chain, from Liljestrand, who nominated all three. Liljestrand noted that thirteen of the first sixteen nominations that came in mentioned Fleming, but only three mentioned him alone. This time evaluations were made by Liljestrand, Sven Hellerström  [ sv ] and Anders Kristenson  [ sv ], who endorsed all three. [58] [59] [60] The Nobel Assembly at the Karolinska Institute considered awarding half to Fleming and one-quarter each to Florey and Chain, but in the end decided to divide it equally three ways. [58] On 25 October 1945, it announced that Fleming, Florey and Chain equally shared the 1945 Nobel Prize in Physiology or Medicine "for the discovery of penicillin and its curative effect in various infectious diseases." [61] [62]

Notes

  1. ↑ Bickel 1995, p. 61.
  2. ↑ "Aboriginal use of fungi". Australian National Herbarium. Retrieved 11 February 2023.
  3. 1 2 3 4 5 6 Lalchhandama, K. (2020). "Reappraising Fleming's Snot and Mould". Science Vision. 20 (1): 29–42. doi: 10.33493/scivis.20.01.03 . ISSN   0975-6175.
  4. ↑ Bigger, J. W.; Boland, C. R.; O'Meara, R. A. (1927). "Variant colonies of Staphylococcus aureu s". The Journal of Pathology and Bacteriology . 30 (2): 261–269. doi:10.1002/path.1700300204. ISSN   0022-3417.
  5. 1 2 3 4 5 Diggins, F. W. (1999). "The true history of the discovery of penicillin, with refutation of the misinformation in the literature". British Journal of Biomedical Science. 56 (2): 83–93. ISSN   0967-4845. PMID   10695047.
  6. 1 2 3 Wainwright, M. (February 1993). "The mystery of the plate: Fleming's discovery and contribution to the early development of penicillin". Journal of Medical Biography . 1 (1): 59–65. doi:10.1177/096777209300100113. ISSN   0967-7720. PMID   11639213. S2CID   7578843.
  7. ↑ Gupta, N.; Rodrigues, C.; Soman, R. (September 2015). "Pioneers in Antimicrobial Chemotherapy". The Journal of the Association of Physicians of India. 63 (9): 90–91. ISSN   0004-5772. PMID   27608881.
  8. 1 2 Greenwood 2008, p. 86.
  9. ↑ Tan, S. Y.; Tatsumura, Y. (July 2015). "Alexander Fleming (1881–1955): Discoverer of penicillin". Singapore Medical Journal . 56 (7): 366–367. doi:10.11622/smedj.2015105. PMC   4520913 . PMID   26243971.
  10. ↑ Arseculeratne, S. N.; Arseculeratne, G. (May 2017). "A re-appraisal of the conventional history of antibiosis and Penicillin". Mycoses . 60 (5): 343–347. doi:10.1111/myc.12599. PMID   28144986. S2CID   21424547.
  11. ↑ Pommerville 2014, p. 807.
  12. ↑ Fleming, Alexander (1929). "On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to their use in the Isolation of B. influenzae". British Journal of Experimental Pathology. 10 (3): 226–236. PMC   2041430 . PMID   2048009.; Reprinted as Fleming, A. (1979). "On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenzae". British Journal of Experimental Pathology. 60 (1): 3–13. PMC   2041430 .
  13. ↑ Fleming 1999, p. 83.
  14. 1 2 3 Hare 1970, pp. 70–74.
  15. ↑ Henderson, J.W. (July 1997). "The yellow brick road to penicillin: a story of serendipity". Mayo Clinic Proceedings . 72 (7): 683–687. doi:10.4065/72.7.683. PMID   9212774.
  16. ↑ Kingston, W (June 2008). "Irish contributions to the origins of antibiotics". Irish Journal of Medical Science. 177 (2): 87–92. doi:10.1007/s11845-008-0139-x. PMID   18347757. S2CID   32847260.
  17. ↑ Thom, C. (1931). "Appendix. History of species used and Dr. Thom's diagnoses of species". Philosophical Transactions of the Royal Society B: Biological Sciences . 220 (468–473): 83–92. doi: 10.1098/rstb.1931.0015 .
  18. ↑ Thom, Charles (1945). "Mycology Presents Penicillin". Mycologia . 37 (4): 460–475. doi:10.2307/3754632. JSTOR   3754632.
  19. ↑ Samson, R.A.; Hadlok, R.; Stolk, A. C. (1977). "A taxonomic study of the Penicillium chrysogenum series". Antonie van Leeuwenhoek. 43 (2): 169–75. doi:10.1007/BF00395671. PMID   413477. S2CID   41843432.
  20. ↑ "International Code of Botanical Nomenclature (VIENNA CODE). Appendix IV Nomina specifica conservanda et rejicienda. B. Fungi". International Association of Plant Taxonomy. 2006. Retrieved 17 June 2020.
  21. ↑ Houbraken, J.; Frisvad, J. C.; Samson, R. A. (June 2011). "Fleming's penicillin producing strain is not Penicillium chrysogenum but P. rubens". IMA Fungus. 2 (1): 87–95. doi:10.5598/imafungus.2011.02.01.12. PMC   3317369 . PMID   22679592.
  22. ↑ Houbraken, J.; Frisvad, J. C.; Seifert, K. A.; Overy, D. P.; Tuthill, D. M.; Valdez, J. G.; Samson, R. A. (December 2012). "New penicillin-producing Penicillium species and an overview of section Chrysogena". Persoonia. 29 (1): 78–100. doi:10.3767/003158512X660571. PMC   3589797 . PMID   23606767.
  23. 1 2 3 Hare, R. (January 1982). "New Light on the History of Penicillin". Medical History . 26 (1): 1–24. doi:10.1017/S0025727300040758. PMC   1139110 . PMID   7047933.
  24. ↑ Wyn Jones, E.; Wyn Jones, R. G. (December 2002). "Merlin Pryce (1902–1976) and Penicillin: An Abiding Mystery". Vesalius. 8 (2): 6–25. ISSN   1373-4857. PMID   12713008.
  25. ↑ Curry, J. (1981). "Obituary: C. J. La Touche". Medical Mycology . 19 (2): 164. doi:10.1080/00362178185380261.
  26. ↑ Wainwright, M.; Swan, H.T. (1987). "The Sheffield penicillin story". Mycologist . 1 (1): 28–30. doi:10.1016/S0269-915X(87)80022-8.
  27. ↑ Wainwright, Milton (1990). "Besredka's "antivirus" in relation to Fleming's initial views on the nature of penicillin". Medical History. 34 (1): 79–85. doi:10.1017/S0025727300050286. PMC   1036002 . PMID   2405221.
  28. ↑ Wainwright, M. (1987). "The history of the therapeutic use of crude penicillin". Medical History . 31 (1): 41–50. doi:10.1017/s0025727300046305. PMC   1139683 . PMID   3543562.
  29. ↑ Wainwright, Milton (1989). "Moulds in Folk Medicine". Folklore. 100 (2): 162–166. doi:10.1080/0015587X.1989.9715763.
  30. ↑ Wainwright, M.; Swan, H.T. (January 1986). "C.G. Paine and the earliest surviving clinical records of penicillin therapy". Medical History. 30 (1): 42–56. doi:10.1017/S0025727300045026. PMC   1139580 . PMID   3511336.
  31. ↑ Alharbi, Sulaiman Ali; Wainwright, Milton; Alahmadi, Tahani Awad; Salleeh, Hashim Bin; Faden, Asmaa A.; Chinnathambi, Arunachalam (2014). "What if Fleming had not discovered penicillin?". Saudi Journal of Biological Sciences. 21 (4): 289–293. doi:10.1016/j.sjbs.2013.12.007. PMC   4150221 . PMID   25183937.
  32. 1 2 Fleming, Alexander (1929). "On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenzae". British Journal of Experimental Pathology. 10 (3): 226–236.; Fleming, A. (1979). "On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenzae". British Journal of Experimental Pathology. 60 (1): 3–13. PMC   2041430 . PMID   2048009. (Reprint)
  33. ↑ "Annotations". The British Medical Journal . 2 (4208): 310–312. August 1941. doi:10.1136/bmj.2.4208.310. ISSN   0959-8138. PMC   2162429 . PMID   20783842.
  34. ↑ Fleming, A. (September 1941). "Penicillin". The British Medical Journal . 2 (4210): 386. doi:10.1136/bmj.2.4210.386. ISSN   0959-8138. PMC   2162878 .
  35. ↑ Williams 1984, p. 67.
  36. ↑ Berger, F. (7 October 1944). "Extraction and Purification of Penicillin". Nature . 154 (3910): 459. Bibcode:1944Natur.154..459B. doi: 10.1038/154459a0 . ISSN   0028-0836. S2CID   4071554.
  37. 1 2 3 MacFarlane 1979, pp. 191–192.
  38. ↑ Wilson 1976, pp. 74–81.
  39. ↑ Jones, David S.; Jones, John H. (2014-12-01). "Sir Edward Penley Abraham CBE. 10 June 1913 – 9 May 1999". Biographical Memoirs of Fellows of the Royal Society . 60: 5–22. doi:10.1098/rsbm.2014.0002. ISSN   0080-4606. S2CID   71557916.
  40. ↑ "Ernst B. Chain – Nobel Lecture: The Chemical Structure of the Penicillins". www.nobelprize.org. Retrieved 2017-05-10.
  41. ↑ Chain 1971, p. 297.
  42. ↑ Hobby 1985, pp. 64–65.
  43. ↑ Wilson 1976, p. 156.
  44. 1 2 MacFarlane 1979, pp. 305–308.
  45. ↑ Mason 2022, pp. 122–123.
  46. 1 2 Wilson 1976, pp. 158–159.
  47. ↑ MacFarlane 1979, pp. 313–316.
  48. ↑ Bickel 1995, pp. 124–129.
  49. ↑ Hodgkin, D. C. (July 1949). "The X-ray analysis of the structure of penicillin". Advancement of Science. 6 (22): 85–89. ISSN   0036-8075. PMID   18134678.
  50. ↑ Curtis, R.; Jones, J. (December 2007). "Robert Robinson and penicillin: an unnoticed document in the saga of its structure". Journal of Peptide Science . 13 (12): 769–775. doi: 10.1002/psc.888 . ISSN   1075-2617. PMID   17890642. S2CID   11213177.
  51. ↑ Williams 1984, pp. 130–132.
  52. ↑ Hobby 1985, pp. 100–101, 234.
  53. ↑ Wilson 1976, pp. 198–200.
  54. ↑ Bickel 1995, p. 187.
  55. ↑ Bickel 1995, p. 173.
  56. ↑ Mason 2022, pp. 274–276.
  57. ↑ Bynum, Bill (2007). "Book and Exhibition: Shedding New light on the Story of Penicillin". The Lancet . 369 (9578): 1991–1992. doi: 10.1016/S0140-6736(07)60929-5 . ISSN   0140-6736. PMID   17577943. S2CID   40981218.
  58. 1 2 3 Norrby 2010, pp. 176–178.
  59. 1 2 Lax 2015, pp. 245–246.
  60. ↑ "Alexander Fleming". Nomination archive. Nobel Foundation. Retrieved 16 February 2023.; "Howard Florey". Nomination archive. Nobel Foundation. Retrieved 16 February 2023.; "Ernst Chain". Nomination archive. Nobel Foundation. Retrieved 16 February 2023.
  61. ↑ "The Nobel Prize in Physiology or Medicine 1945". Nobel Foundation. Retrieved 2020-07-26.
  62. ↑ Lax 2015, p. 247.

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Howard Walter Florey, Baron Florey, was an Australian pharmacologist and pathologist who shared the Nobel Prize in Physiology or Medicine in 1945 with Ernst Chain and Sir Alexander Fleming for his role in the development of penicillin.

<span class="mw-page-title-main">Mold</span> Wooly, dust-like fungal structure or substance

A mold or mould is one of the structures that certain fungi can form. The dust-like, colored appearance of molds is due to the formation of spores containing fungal secondary metabolites. The spores are the dispersal units of the fungi. Not all fungi form molds. Some fungi form mushrooms; others grow as single cells and are called microfungi.

<span class="mw-page-title-main">Beta-lactam antibiotics</span> Class of broad-spectrum antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were β-lactam compounds. The first β-lactam antibiotic discovered, penicillin, was isolated from a strain of Penicillium rubens.

<i>Penicillium</i> Genus of fungi

Penicillium is a genus of ascomycetous fungi that is part of the mycobiome of many species and is of major importance in the natural environment, in food spoilage, and in food and drug production.

<span class="mw-page-title-main">Ernst Chain</span> German-born British biochemist (1906–1979)

Sir Ernst Boris Chain was a German-born British biochemist and co-recipient of the Nobel Prize in Physiology or Medicine for his work on penicillin.

<span class="mw-page-title-main">Edward Abraham</span> English biochemist (1913–1999)

Sir Edward Penley Abraham, was an English biochemist instrumental in the development of the first antibiotics penicillin and cephalosporin.

<span class="mw-page-title-main">Glucose oxidase</span> Class of enzymes

The glucose oxidase enzyme also known as notatin is an oxidoreductase that catalyses the oxidation of glucose to hydrogen peroxide and D-glucono-δ-lactone. This enzyme is produced by certain species of fungi and insects and displays antibacterial activity when oxygen and glucose are present.

Martin Henry Dawson was a Canadian researcher who made important contributions in the fields of infectious diseases.

<span class="mw-page-title-main">History of penicillin</span> Aspect of medical history

The history of penicillin follows observations and discoveries of evidence of antibiotic activity of the mould Penicillium that led to the development of penicillins that became the first widely used antibiotics. Following the production of a relatively pure compound in 1942, penicillin was the first naturally-derived antibiotic.

Reserve Constable Albert Alexander was the first patient to be treated with injections of penicillin.

<span class="mw-page-title-main">Medical microbiology</span> Branch of medical science

Medical microbiology, the large subset of microbiology that is applied to medicine, is a branch of medical science concerned with the prevention, diagnosis and treatment of infectious diseases. In addition, this field of science studies various clinical applications of microbes for the improvement of health. There are four kinds of microorganisms that cause infectious disease: bacteria, fungi, parasites and viruses, and one type of infectious protein called prion.

<span class="mw-page-title-main">Phenoxymethylpenicillin</span> Antibiotic medication

Phenoxymethylpenicillin, also known as penicillin V (PcV) and penicillin VK, is an antibiotic useful for the treatment of a number of bacterial infections. Specifically it is used for the treatment of strep throat, otitis media, and cellulitis. It is also used to prevent rheumatic fever and to prevent infections following removal of the spleen. It is given by mouth.

Pharmaceutical engineering is a branch of engineering focused on discovering, formulating, and manufacturing medication, analytical and quality control processes, and on designing, building, and improving manufacturing sites that produce drugs. It utilizes the fields of chemical engineering, biomedical engineering, pharmaceutical sciences, and industrial engineering.

<i>Penicillium chrysogenum</i> Species of fungus

Penicillium chrysogenum is a species of fungus in the genus Penicillium. It is common in temperate and subtropical regions and can be found on salted food products, but it is mostly found in indoor environments, especially in damp or water-damaged buildings. It has been recognised as a species complex that includes P. notatum, P. meleagrinum, and P. cyaneofulvum. Molecular phylogeny has established that Alexander Fleming's first discovered penicillin producing strain is of a distinct species, P. rubens, and not of P. notatum. It has rarely been reported as a cause of human disease. It is the source of several β-lactam antibiotics, most significantly penicillin. Other secondary metabolites of P. chrysogenum include roquefortine C, meleagrin, chrysogine, 6-MSA YWA1/melanin, andrastatin A, fungisporin, secalonic acids, sorbicillin, and PR-toxin.

<span class="mw-page-title-main">Charles Thom</span> American icrobiologist and mycologist (1872–1956)

Charles Thom was an American microbiologist and mycologist. Born and raised in Illinois, he received his PhD from the University of Missouri, the first such degree awarded by that institution. He studied the microbiology of dairy products and soil fungi, and in particular researched the genera Aspergillus and Penicillium. His work influenced the establishment of standards for food handling and processing in the USA. He pioneered the use of culture media to grow microorganisms, and, with food chemist James N. Currie, developed a process to mass-produce citric acid using Aspergillus. Thom played an important role in the development of penicillin in World War II.

<i>Penicillium rubens</i> Species of fungus

Penicillium rubens is a species of fungus in the genus Penicillium and was the first species known to produce the antibiotic penicillin. It was first described by Philibert Melchior Joseph Ehi Biourge in 1923. For the discovery of penicillin from this species Alexander Fleming shared the Nobel Prize in Physiology or Medicine in 1945. The original penicillin-producing type has been variously identified as Penicillium rubrum, P. notatum, and P. chrysogenum among others, but genomic comparison and phylogenetic analysis in 2011 resolved that it is P. rubens. It is the best source of penicillins and produces benzylpenicillin (G), phenoxymethylpenicillin (V) and octanoylpenicillin (K). It also produces other important bioactive compounds such as andrastin, chrysogine, fungisporin, roquefortine, and sorbicillins.

<span class="mw-page-title-main">Bacteriologist</span> Professional trained in bacteriology

A bacteriologist is a microbiologist, or similarly trained professional, in bacteriology— a subdivision of microbiology that studies bacteria, typically pathogenic ones. Bacteriologists are interested in studying and learning about bacteria, as well as using their skills in clinical settings. This includes investigating properties of bacteria such as morphology, ecology, genetics and biochemistry, phylogenetics, genomics and many other areas related to bacteria like disease diagnostic testing. Alongside human and animal healthcare providers, they may carry out various functions as medical scientists, veterinary scientists, pathologists, or diagnostic technicians in locations like clinics, blood banks, hospitals, laboratories and animal hospitals. Bacteriologists working in public health or biomedical research help develop vaccines for public use as well as public health guidelines for restaurants and businesses.

References

Open Access logo PLoS transparent.svg This article was submitted to WikiJournal of Medicine for external academic peer review in 2021 ( reviewer reports ). The updated content was reintegrated into the Wikipedia page under a CC-BY-SA-3.0 license ( 2021 ). The version of record as reviewed is: Kholhring Lalchhandama; et al. (22 October 2021), "History of penicillin" (PDF), WikiJournal of Medicine, 8 (1): 3, doi:10.15347/WJM/2021.003, ISSN   2002-4436, Wikidata   Q107303937 {{cite journal}}: CS1 maint: unflagged free DOI (link)

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