History of penicillin

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The core structure of penicillin, where R is a variable group

Fleming's mould, Penicillium rubens CBS 205.57. A–C. Colonies 7 d old 25 °C. A. CYA. B. MEA. C. YES. D–H.
Condiophores. I. Conidia. Bars = 10 µm.

The history of penicillin follows a number of observations and discoveries of apparent

evidence of antibiotic activity of the mould Penicillium. Following the identification
of Penicillium rubens as the source of the compound in 1928 and with the production of
pure compound in 1942, penicillin became the first naturally derived antibiotic. There
are anecdotes about ancient societies using moulds to treat infections, and in the
following centuries many people observed the inhibition of bacterial growth by various
moulds.[1] However, it is unknown if the species involved were Penicillium species or if
the antimicrobial substances produced were penicillin.
While working at St Mary's Hospital in London, Scottish physician Alexander
Fleming was the first to experimentally discover that a Penicillium mould secretes an
antibacterial substance, and the first to concentrate the active substance involved,
which he named penicillin in 1928.[2][3] The mould was determined to be a rare variant
of Penicillium notatum (now Penicillium rubens), a laboratory contaminant in his lab.
  For the next 16 years, he studied on methods of better production of penicillin,
[4]

medicinal uses and clinical trial. His successful treatment of Harry Lambert who had
fatal streptococcal meningitis in 1942 proved to be a critical moment in the medical
usage of penicillin.
Many later scientists were involved in the stabilization and mass production of penicillin
and in the search for more productive strains of Penicillium.[5] Important contributors
include Ernst Chain, Howard Florey, Norman Heatley and Edward Abraham.[2] Fleming,
Florey and Chain shared the 1945 Nobel Prize in Physiology or Medicine for the
discovery and development of penicillin. [6] Dorothy Hodgkin received the 1964 Nobel
Prize in Chemistry determining the structures of important biochemical substances
including penicillin. Shortly after the discovery of penicillin, there were reports of
penicillin resistance in many bacteria. Research that aims to circumvent and understand
the mechanisms of antibiotic resistance continues today.[7][8]

Contents

 1Early history
 2Early scientific evidence
 3The breakthrough discovery
o 3.1Background
o 3.2Initial discovery
o 3.3Experiment
o 3.4Identification of the mould
o 3.5Reception and publication
 4First medical use
 5Isolation and mass production
o 5.1Manufacturing
o 5.2Structure determination
o 5.3Outcomes
 6Development of penicillin-derivatives
 7Drug resistance
 8Notes
 9References
 10Further reading
 11External links

Early history[edit]
Many ancient cultures, including those in Egypt, Greece and India, independently
discovered the useful properties of fungi and plants in treating infection.[9] 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.
In 17th-century Poland, wet bread was mixed with spider webs (which often contained
fungal spores) to treat wounds. The technique was mentioned by Henryk Sienkiewicz in
his 1884 book With Fire and Sword. In England in 1640, the idea of using mould as a
form of medical treatment was recorded by apothecaries such as John Parkinson,
King's Herbarian, who advocated the use of mould in his book on pharmacology.[10]

Early scientific evidence[edit]

NB
In the early stages of penicillin research, most species of Penicillium were
generally referred to as Penicillium glaucum, so we cannot identify the actual
strains used. Thus, it is difficult to tell whether it was really penicillin preventing
bacterial growth.[11]
The modern history of penicillin research begins in earnest in the 1870s in the
United Kingdom. Sir John Scott Burdon-Sanderson, who started out at St. Mary's
Hospital (1852–1858) and later worked there as a lecturer (1854–1862), observed
that culture fluid covered with mould would produce no bacterial growth. Burdon-
Sanderson's discovery prompted Joseph Lister, an English surgeon and the father
of modern antisepsis, to discover in 1871 that urine samples contaminated with
mould also did not permit the growth of bacteria. Lister also described the
antibacterial action on human tissue of a species of mould he called Penicillium
glaucum.[12] A nurse at King's College Hospital whose wounds did not respond to any
traditional antiseptic was then given another substance that cured him, and Lister's
registrar informed him that it was called Penicillium. In 1874, the Welsh
physician William Roberts, who later coined the term "enzyme", observed that
bacterial contamination is generally absent in laboratory cultures of Penicillium
glaucum. John Tyndall followed up on Burdon-Sanderson's work and demonstrated
to the Royal Society in 1875 the antibacterial action of the Penicillium fungus.[13]
By this time, Bacillus anthracis had been shown to cause anthrax, the first
demonstration that a specific bacterium caused a specific disease. In 1877, French
biologists Louis Pasteur and Jules Francois Joubert observed that cultures of the
anthrax bacilli, when contaminated with moulds, could be successfully inhibited.
Some references say that Pasteur identified the strain as Penicillium notatum.
However, Paul de Kruif's 1926 Microbe Hunters describes this incident as
contamination by other bacteria rather than by mould. [14] In 1887, Garré found similar
results. In 1895, Vincenzo Tiberio, an Italian physician at the University of Naples,
published research about moulds initially found in a water well in Arzano; from his
observations, he concluded that these moulds contained soluble substances having
antibacterial action.[15][16][17][18]
Two years later, Ernest Duchesne at École du Service de Santé Militaire
in Lyon independently discovered the healing properties of a Penicillium
glaucum mould, even curing infected guinea pigs of typhoid. He published a
dissertation[19][20][21] in 1897 but it was ignored by the Institut Pasteur. Duchesne was
himself using a discovery made earlier by Arab stable boys, who used 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. The penicillin
isolated by Fleming does not cure typhoid and so it remains unknown which
substance might have been responsible for Duchesne's cure. [a]
In Belgium in 1920, 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 the fungus as a species of Penicillium and presented their
observations as a paper, but it received little attention. An Institut Pasteur
scientist, Costa Rican Clodomiro Picado Twight, similarly recorded the antibiotic
effect of Penicillium in 1923.

The breakthrough discovery[edit]

Background[edit]
Alexander Fleming in his laboratory at St Mary's Hospital, London

Penicillin was discovered by a Scottish physician Alexander Fleming in 1928. While

working at St Mary's Hospital, London, Fleming was investigating the pattern of
variation in S. aureus.[22] 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 the Trinity College, Dublin, Ireland, in 1927. Bigger and his students
found that when they cultured a particular strain of S. aureus, which they designated
"Y" that they isolated a year before from a pus of axillary abscess from one
individual, 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, by 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.[23]
Fleming and his research scholar Daniel Merlin Pryce pursued this experiment but
Pryce was transferred to another laboratory in the 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 by the end of 1928.[22]
Initial discovery[edit]
In August, Fleming spent a vacation 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 in a
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.[24] 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.
  Fleming commented as he watched the plate: "That's funny". [24][26] Pryce remarked
[25]

to Fleming: "That's how you discovered lysozyme."[27]