History of penicillin
In 1895, Vincenzo Tiberio, an Italian physician at the University of Naples, published research on moulds found in a water well in Arzano. He concluded that these moulds contained soluble substances having antibacterial action. A Pasteur Institute scientist named Costa Rican Clodomiro Picado Twight recorded the antibiotic effect of Penicillium in 1923. Andre Gratia and Sara Dath at the Free University of Brussels studied mould samples on bacteria in 1924. They found that dead Staphylococcus aureus cultures were contaminated by a mould called streptomycete. Their experiments showed the mould extract could kill Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Escherichia coli. Gratia called this antibacterial agent mycolysate. The next year they identified another killer mould that inhibited B. anthracis. These findings received little attention because the medical value was not fully understood. Ancient cultures including those in Australia, China, Egypt, Greece, and India independently discovered useful properties of fungi for treating infections. However, ancient practitioners could not identify or isolate the active components in these organisms.
While working at St Mary's Hospital in London in 1928, Scottish physician Alexander Fleming investigated variation in growth of S. aureus cultures. He spent his summer break with family at The Dhoon country home in Barton Mills, Suffolk. Before leaving his laboratory at the end of July, he inoculated several culture plates with S. aureus. He kept the plates aside on one corner of the table to make space for research student Stuart Craddock. Fleming returned to his laboratory on the 3rd of September. He and Daniel Merlin Pryce examined the culture plates and found one with an open lid contaminated by blue-green mould. In the contaminated plate bacteria around the mould did not grow while those farther away grew normally. Fleming photographed the culture and took a sample of the mould for identification. After four days he found large colonies of the mould developed. He repeated the experiment with the same bacteria-killing results. He concluded the mould released a substance inhibiting bacterial growth. On testing against different bacteria, he found the mould killed only certain Gram-positive bacteria like Staphylococcus, Streptococcus, and diphtheria bacillus. There was no effect on typhoid bacterium or Haemophilus influenzae. He prepared a culture method to obtain mould juice which he called penicillin on the 7th of March 1929. Fleming reported findings to the British Journal of Experimental Pathology on the 10th of May 1929. The article failed to attract much attention.
In 1939 at Sir William Dunn School of Pathology at University of Oxford, Ernst Boris Chain drew attention of professor Howard Florey to Fleming's largely forgotten 1929 paper. Florey led interdisciplinary team including Edward Abraham, Mary Ethel Florey, Norman Heatley, Margaret Jennings, Jean Orr-Ewing, and Gordon Sanders. Each member tackled particular aspect in area of expertise. Florey approached Medical Research Council secretary Edward Mellanby for support in September 1939. Mellanby authorized project allocating £250 with £300 for salaries and £100 for expenses per annum for three years. On the 1st of November 1939 Henry M. Dusty Miller Jr from Rockefeller Foundation paid Florey visit. Miller encouraged Florey to apply for funding from foundation. Foundation allocated US$5,000 per annum for five years. Georges Dreyer had obtained sample of mould in 1930 but lost interest when he discovered it was not bacteriophage. Campbell-Renton continued culturing mould and supplied it to Oxford team. Mould cultured on surface of liquid Czapek-Dox medium formed yellow gelatinous skin covered in green spores. Liquid beneath became yellow containing penicillin. Maximum yield achieved in ten to twenty days. Bedpan found practical basis for specially-made ceramic containers fabricated by J. Macintyre and Company in Burslem. Containers rectangular shape could be stacked to save space. Heatley collected first 174 of order for 500 vessels on the 22nd of December 1940. They were seeded with spores three days later. Team tried adding brewing yeast which cut incubation time by third. Abraham and Chain discovered airborne bacteria produced penicillinase enzyme destroying penicillin. Liquid filtered through parachute silk removing mycelium and debris. Solution acidified by addition of phosphoric acid. Chain determined penicillin stable only pH between 5 and 8. Keeping mixture at 0°C retarded breakdown process. Ether used initially as solvent but highly inflammable and toxic. Amyl acetate much less flammable also worked. Heatley developed continuous extraction process called reverse extraction using sodium hydroxide. Chain hit upon idea of freeze drying recently developed in Sweden enabling water removal resulting dry brown powder. Heatley developed penicillin assay using agar nutrient plates. Short glass cylinders containing fluid placed on nutrient plates incubated 12 to 16 hours at 37°C. Diameter of ring indicated strength of penicillin. Oxford unit defined purity required produce 25 mm bacteria-free ring.
Knowing large-scale production futile in laboratory, Oxford team tried convince war-torn British government and private companies engage mass production. Initial response muted. Dr Blount director research at Glaxo Laboratories wrote Florey September 1940 receiving no reply. Florey had appealed assistance two British pharmaceutical companies turned down. In April 1941 Warren Weaver met Florey discussing difficulty producing sufficient penicillin for clinical trials. Weaver arranged Rockefeller Foundation fund three-month visit United States for Florey and colleague explore possibility production there. Florey and Heatley left United States by air the 27th of June 1941. They smeared coat pockets mould samples avoid loss. Florey met neurophysiologist John Fulton introducing him Ross Harrison chairman National Research Council. Harrison referred Florey to Thom chief mycologist Bureau Plant Industry United States Department Agriculture Beltsville Maryland. On the 9th of July Thom took Florey and Heatley Washington DC meet Percy Wells acting assistant chief USDA Bureau Agricultural Industrial Chemistry. Wells sent introductory telegram Orville May director UDSA Northern Regional Research Laboratory Peoria Illinois. They met May the 14th of July arranging meeting Robert D. Coghill chief NRRL fermentation division raising possibility fermentation large vessels key large-scale production. On the 17th of August Florey met Alfred Newton Richards chairman Committee Medical Research Office Scientific Research Development promising support. On the 8th of October Richards held meeting representatives four major pharmaceutical companies Squibb, Merck, Pfizer Lederle. Vannevar Bush director OSRD present as was Thom representing NRRL. Richards told antitrust laws suspended allowing sharing information about penicillin. This not legalized until the 7th of December 1943 covering only penicillin no other drug. OSRD arranged War Production Board priority equipment laboratories pilot plants. Coghill made Andrew J. Moyer available work penicillin with Heatley while Florey left arrange pharmaceutical company manufacture penicillin. As first step increasing yield Moyer replaced sucrose growth media lactose. Even larger increase occurred when Moyer added corn steep liquor byproduct corn industry NRRL routinely tried finding more uses it. Effect dramatic; Heatley Moyer found increased yield tenfold. Anne Sheafe Miller wife Yale University athletics director Ogden D. Miller succumbing streptococcal septicaemia contracted miscarriage March 1942. Her doctor John Bumstead treating John Fulton infection time knew Fulton knew Florey children staying him. He went Fulton plead penicillin. Florey returned UK Heatley still United States working Merck. Phone call Richards released 5.5 grams penicillin earmarked clinical trial despatched Washington DC air. Effect dramatic; within 48 hours fever abated eating again. Blood culture count dropped 100 to 150 bacteria colonies per millilitre just one. Miller full recovery lived until 1999.
Dorothy Hodgkin determined correct chemical structure of penicillin using X-ray crystallography at Oxford in 1945. Chemical structure first suggested Abraham 1942. In 1945 US Committee Medical Research British Medical Council jointly published Science chemical analyses conducted different universities pharmaceutical companies government research departments. Report announced existence different forms penicillin compounds sharing same structural component called beta-lactam. Penicillins designated Roman numerals UK Penicillin I, II, III IV order discoveries known letters F, G, X K referring origins sources US. Chemical names based side chains compounds. In 1948 Chain introduced chemical names standard nomenclature remarking make nomenclature far possible unambiguous. Hans Margreiter Ernst Brandl Biochemie developed first acid-stable penicillin oral administration penicillin V Kundl Tyrol Austria 1952. American chemist John C. Sheehan Massachusetts Institute Technology completed first chemical synthesis penicillin V 1957. Sheehan started studies penicillin synthesis 1948 developing new methods synthesis peptides new protecting groups masking reactivity certain functional groups. Initial synthesis Sheehan not appropriate mass production penicillins one intermediate compound 6-aminopenicillanic acid 6-APA nucleus penicillin. Important development discovery 6-APA itself. In 1957 researchers Beecham Research Laboratories Surrey isolated 6-APA culture media P. chrysogenum. 6-APA found constitute core nucleus penicillin subsequently many beta-lactam antibiotics easily chemically modified attaching side chains through chemical reactions. Discovery published Nature 1959 paving way new improved drugs semisynthetic penicillins produced chemical manipulation 6-APA.
Narrow range treatable diseases spectrum activity poor activity orally active penicillin V led search derivatives penicillin treating wider range infections. Second-generation semisynthetic beta-lactam antibiotic methicillin designed counter first-generation-resistant penicillinases introduced United Kingdom 1959. Methicillin-resistant forms S. aureus MRSA first observed UK 1960 less year later. Likely MRSA strains existed many years before methicillin introduced. Demonstrated new drugs intended circumvent known resistance mechanisms rendered ineffective bacterial adaptations caused widespread use other antibiotics. Penicillin added animal feed increased weight gain improved feed-conversion efficiency promoted uniform growth facilitated disease control. Agriculture became major user penicillin. Shortly after discovery Oxford team reported penicillin resistance many bacteria. Research aims circumvent understand mechanisms antibiotic resistance continues. By 1948 Japan third country US UK self-sufficient penicillin exports China Korea began following year. In Italy Domenico Marotta negotiated UNRRA penicillin plant built near Sapienza University Rome construction commenced 1948. Chain came Istituto Superiore di Sanità deliver series lectures Marotta recruited colleague Chain suggested instead building pilot plant use UNRRA money build institute research penicillin. Became largest kind world over hundred chemists biochemists microbiologists technicians soon forefront research semisynthetic penicillin. In 1947 ICI decided construct new plant produce penicillin per day deep submergence method. Glaxo Laboratories opened small production plant Greenford December 1942 producing 70 litres penicillin broth per week. February 1943 opened second plant Aylesbury initially used techniques developed Oxford September 1943 switched using corn steep liquor medium switching NRRL 1249.B21 strain mould provided Coghill. In 1943 Glaxo responsible 2,570 million 3,500 million Oxford units produced UK. Glaxo opened third factory Watford February 1944 fourth Stratford London January 1945 company responsible 80 percent UK output June 1944.
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Common questions
Who discovered penicillin and when was it first identified?
Scottish physician Alexander Fleming discovered penicillin on the 3rd of September 1928 while working at St Mary's Hospital in London. He published his findings in the British Journal of Experimental Pathology on the 10th of May 1929.
When did the Oxford team begin developing large-scale production methods for penicillin?
Ernst Boris Chain and Howard Florey began their project at Sir William Dunn School of Pathology at University of Oxford in 1939. They secured funding from the Medical Research Council in September 1939 and received support from the Rockefeller Foundation later that year.
How was penicillin mass produced during World War II?
The Oxford team collaborated with American pharmaceutical companies including Pfizer, Merck, Squibb, and Lederle to develop fermentation techniques. Researchers used corn steep liquor to increase yield tenfold and employed reverse extraction processes to purify the drug for clinical use.
What is the chemical structure of penicillin and who determined it?
Dorothy Hodgkin determined the correct chemical structure of penicillin using X-ray crystallography at Oxford in 1945. The compound contains a beta-lactam ring which serves as the core nucleus for all penicillins and related antibiotics.
When were semisynthetic penicillins developed and why were they created?
Researchers developed second-generation semisynthetic beta-lactam antibiotic methicillin in the United Kingdom in 1959 to counter resistant bacteria. This innovation allowed scientists to attach side chains to the 6-aminopenicillanic acid nucleus to create drugs effective against strains like MRSA.