Penicillin core structure, where "R" is the variable group.
Prior to 1928, the History of penicillin is unclear. A number of people observed the inhibition of bacterial growth by moulds. There are anecdotes about ancient societies using moulds to treat infection.[1] However, it is unknown if the species involved were Penicillium species, or if the antimicrobial substances produced were penicillin.
Alexander Fleming was the first to suggest that a Penicillium mould must secrete an antibacterial substance, and the first to concentrate the active substance involved, which he named penicillin, in 1928. Penicillin was the first modern antibiotic. During the next twelve years Fleming grew, distributed, and studied the original mould, which was determined to be a rare variant of Penicillium notatum (now Penicillium chrysogenum).[2][3]
Many later scientists were involved in the stabilization and mass production of penicillin, and in the search for more productive strains of Penicillium.[4] Important contributors include Ernst Chain, Howard Florey, Norman Heatley, and Edward Abraham.[2]
Closely following on the discovery of penicillin, scientists found that some diseases display antibiotic resistance to penicillin. This has led to attempts to develop more effective strains, and to studies of the causes and mechanisms of antibiotic resistance.[5][6]
Observations of the inhibiting properties of moulds[edit]
Year
Location
Descriptions
Ancient times
Egypt, Greece & India
Many ancient cultures, including the ancient Egyptians, Greeks and in ancient India, already used moulds and other plants to treat infection.[7] This worked because some moulds produce antibiotic substances. However, they could not identify or isolate the active component in the moulds.
c. 150 BC
Sri Lanka
Soldiers in the army of king Dutugemunu (161–137 BC) are recorded to have stored oil cakes (a traditional Sri Lankan sweetmeat) for long periods in their hearth lofts before embarking on their campaigns, in order to make a poultice of the cakes to treat wounds.[citation needed]
The idea of using mould as a form of treatment was recorded by apothecaries, such as John Parkinson, King's Herbarian, who advocated the use of mould in his book on pharmacology.[citation needed]
1870
United Kingdom
Sir John Scott Burdon-Sanderson, who started out at St. Mary's Hospital 1852–1858 and as lecturer there 1854–1862 observed that culture fluid covered with mould would produce no bacteria.
1871
United Kingdom
Burdon-Sanderson's discovery prompted Joseph Lister, an English surgeon and the father of modern antisepsis to investigate that urine samples contaminated with mould did not allow the growth of bacteria. He also described the antibacterial action on human tissue of what he called Penicillium glaucum.[8] A nurse at King's College Hospital whose wounds did not respond to any antiseptic, was then given another substance that cured her, and Lister's registrar informed her that it was called Penicillium.
Ernest Duchesne at École du Service de Santé Militaire in Lyon independently discovered healing properties of a Penicillium glaucum mould, even curing infected guinea pigs of typhoid. He published a dissertation[14][15][16] in 1897 but this was ignored by the Institut Pasteur. However Duchesne was himself using a discovery made by Arab stable boys, who were using moulds to cure sores on horses. He did not claim that the mould contained any antibacterial substance, only that the mould somehow protected the animals.
Duchesne cured typhoid, but the penicillin isolated by Fleming does not cure typhoid.
Duchesne injected a mould with the fungus Penicillium glaucum. In contrast, Fleming isolated the substance penicillin from the mould Penicillium notatum.
The term Penicillium glaucum was used as a catch-all phrase at the time for different fungi, but not for Penicillium notatum and the mould was unfortunately not preserved, which makes it impossible to be certain today which fungus might have been responsible for the cure, and consequently, even less certain which substance was responsible.
1920
Belgium
Andre Gratia and Sara Dath observed a fungal contamination in one of their Staphylococcus aureus cultures that was inhibiting the growth of the bacterium. They identified this as a species of Penicillium and presented their observations as a paper. There was little attention to this paper.
Scottish biologist Sir Alexander Fleming noticed a halo of inhibition of bacterial growth around a contaminant blue-green mould on a Staphylococcus plate culture. He concluded that the mould was releasing a substance that was inhibiting bacterial growth. He grew a pure culture of the mould and concentrated what he later named "penicillin". During the next twelve years, he grew and distributed the original mould, which was eventually identified as Penicillium notatum (now known as Penicillium chrysogenum). He was unsuccessful in making a stable form of it, for mass production.[17]
1930
United Kingdom
Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, attempted to treat sycosis (eruptions in beard follicles) with penicillin but was unsuccessful, probably because the drug did not penetrate deep enough. Moving on to ophthalmia neonatorum, a gonococcal infection in babies, he achieved the first cure on 25 November 1930. He cured four patients (one adult, the others babies) of eye infections, although a fifth patient was not so lucky.[18]
In Oxford, Howard Walter Florey organized his large and very skilled biochemical research team, notable among them Ernst Boris Chain and Norman Heatley, to undertake clinical trials and produce a stable penicillin.
Peoria, Illinois: Moyer, Coghill and Raper at the USDANorthern Regional Research Laboratory
(NRRL) developed methods for industrialized penicillin production and isolated higher-yielding strains of the Penicillium fungus.[20][21] In December, 1942 survivors of the Cocoanut Grove fire in Boston were the first burn patients to be successfully treated with penicillin.[22]
Kundl, Tyrol: Hans Margreiter and Ernst Brandl of Biochemie (now Sandoz) developed the first acid-stable penicillin for oral administration, Penicillin V.[27]
Introduction of the second-generation semi-synthetic β-lactam antibiotic methicillin, designed to counter first-generation-resistant penicillinases. Methicillin-resistant forms of Staphylococcus aureus likely already existed.[5][29]
^Tiberio, Vincenzo (1895) "Sugli estratti di alcune muffe" [On the extracts of certain moulds], Annali d'Igiene Sperimentale (Annals of Experimental Hygiene), 2nd series, 5 : 91–103. From p. 95:"Risulta chiaro da queste osservazioni che nella sostanza cellulare delle muffe esaminate son contenuti dei principi solubili in acqua, forniti di azione battericida: sotto questo riguardo sono più attivi o in maggior copia quelli dell' Asp. flavescens, meno quelli del Mu. mucedo e del Penn. glaucum." (It follows clearly from these observations that in the cellular substance of the moulds examined are contained some water-soluble substances, provided with bactericidal action: in this respect are more active or in greater abundance those of Aspergillus flavescens; less, those of Mucor mucedo and Penicillium glaucum.)
^HODGKIN, D. C. (July 1949). "The X-ray analysis of the structure of penicillin". Advancement of science. 6 (22): 85–9. PMID18134678.
^Curtis, Rachel; Jones, John (2007). "Robert Robinson and penicillin: an unnoticed document in the saga of its structure". Journal of Peptide Science. 13: 769–775. doi:10.1002/psc.888.
Brown, Kevin W. (St Mary's Trust Archivist and Alexander Fleming Laboratory Museum Curator) (2004). Penicillin man: Alexander Fleming and the antibiotic revolution. Scarborough, Ont: Sutton Pub. ISBN0-7509-3152-3. (Most of the information in this article comes from this book)
. PMID 3511336.
