Natural Science Forum / Biology / Microbiology / July 2008

If it took many decades for the experts to accept bread mould /
penicillin could save millions of lives  , How long will it take the
"experts" to accept old tin cans /. "iron fertilization" will cure
global warming and feed billions
http://en.wikipedia.org/wiki/Penicillin#Discovery_and_history

Iron fertilization - Wikipedia, the free encyclopedia

Iron fertilization is the intentional introduction of iron to the
upper ocean to increase the marine food chain and to sequester carbon
dioxide from the ...
www.en.wikipedia.org/wiki/Iron_fertilization

The discovery of penicillin is attributed to Scottish scientist Sir
Alexander Fleming in 1928 and the development of penicillin for use as
a medicine is attributed to the Australian Nobel Laureate Howard
Walter Florey.
http://en.wikipedia.org/wiki/Penicillin#Discovery_and_history

However, several others had noted earlier the bacteriostatic effects
of Penicillium: The first published reference appears to have been in
1875, when it was reported to the Royal Society in London by John
Tyndall[1]. Ernest Duchesne documented it in his 1897 paper; however
it was not accepted by the Institut Pasteur because of his young age.
In March 2000, doctors at the San Juan de Dios Hospital in San Jose
(Costa Rica) published manuscripts belonging to the Costa Rican
scientist and medical doctor Clodomiro (Clorito) Picado Twight
(1887-1944). The manuscripts explained Picado's experiences between
1915 and 1927 about the inhibitory actions of the fungi of genera
Penic. Clorito Picado had reported his discovery to the Paris Academy
of Sciences, yet did not patent it, even though his investigation had
started years before Fleming's.

Fleming recounted later that the date of his breakthrough was on the
morning of Tuesday, September 28, 1928[2]. At his laboratory in the
basement of St. Mary's Hospital in London (now part of Imperial
College), Fleming noticed a halo of inhibition of bacterial growth
around a contaminant blue-green mold Staphylococcus plate culture.
Fleming concluded that the mold was releasing a substance that was
inhibiting bacterial growth and lysing the bacteria. He grew a pure
culture of the mold and discovered that it was a Penicillium mold, 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 culture of the
Penicillium mold. Even in these early stages, penicillin was found to
be most effective against Gram-positive bacteria, and ineffective
against Gram-negative organisms and fungi. He expressed initial
optimism that penicillin would be a useful disinfectant, being highly
potent with minimal toxicity compared to antiseptics of the day, but,
in particular, noted its laboratory value in the isolation of
"Bacillus influenzae" (now Haemophilus influenzae)[3]. After further
experiments, Fleming was convinced that penicillin could not last long
enough in the human body to kill pathogenic bacteria, and stopped
studying penicillin after 1931, but restarted some clinical trials in
1934 and continued to try to get someone to purify it until 1940[4].

In 1930 Cecil George Paine, a pathologist at the Royal Infirmary in
Sheffield, attempted to treat sycosis - eruptions in beard follicles -
but was unsuccessful, probably because the drug did not get 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, three babies) of eye infections, although a fifth
patient was not so lucky[5].

In 1939, Australian scientist Howard Florey (later Baron Florey) and a
team of researchers (Ernst Boris Chain, A. D. Gardner, Norman Heatley,
M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn
School of Pathology, University of Oxford made significant progress in
showing the in vivo bactericidal action of penicillin. Their attempts
to treat humans failed due to insufficient volumes of penicillin (the
first patient treated was Reserve Constable Albert Alexander), but
they proved it harmless and effective on mice[6].

Some of the pioneering trials of penicillin took place at the
Radcliffe Infirmary in Oxford. On March 14, 1942, John Bumstead and
Orvan Hess became the first in the world to successfully treat a
patient using penicillin[7][8].

The challenge of mass-producing the drug had been daunting. On March
14, 1942 the first patient was successfully treated for streptococcal
septicemia with U.S.-made penicillin. Half of the total supply
produced at the time was used on that one patient. By June 1942 there
was just enough U.S. penicillin available to treat ten patients[9]. A
moldy cantaloupe in a Peoria, Illinois market in 1943 was found to
contain the best and highest-quality penicillin after a world-wide
search[10]. The discovery of the cantaloupe, and the results of
fermentation research on corn-steep liquid at the Northern Regional
Research Laboratory at Peoria, Illinois, allowed the USA to produce
2.3 million doses in time for the invasion of Normandy in the spring
of 1944.
Penicillin was being mass-produced in 1944
Penicillin was being mass-produced in 1944

During World War II, penicillin made a major difference in the number
of deaths and amputations caused by infected wounds among Allied
forces, saving an estimated 12%-15% of lives.[citation needed]
Availability was severely limited, however, by the difficulty of
manufacturing large quantities of penicillin and by the rapid renal
clearance of the drug, necessitating frequent dosing. Penicillins are
actively secreted, and about 80% of a penicillin dose is cleared
within three to four hours of administration. During those times, it
became common procedure to collect the urine from patients being
treated so that the penicillin could be isolated and reused[11].

This was not a satisfactory solution, however; so researchers looked
for a way to slow penicillin secretion. They hoped to find a molecule
that could compete with penicillin for the organic acid transporter
responsible for secretion such that the transporter would
preferentially secrete the competitive inhibitor. The uricosuric agent
probenecid proved to be suitable. When probenecid and penicillin are
concomitantly administered, probenecid competitively inhibits the
secretion of penicillin, increasing penicillin's concentration and
prolonging its activity. The advent of mass-production techniques and
semi-synthetic penicillins solved supply issues, and this use of
probenecid declined.[11] Probenecid is still useful, however, for
certain infections requiring particularly high concentrations of
penicillins[12].

The chemical structure of penicillin was determined by Dorothy
Crowfoot Hodgkin in the early 1940s. A team of Oxford research
scientists led by Australian Howard Florey, Baron Florey and including
Ernst Boris Chain and Norman Heatley discovered a method of mass-
producing the drug. Chemist John Sheehan at MIT completed the first
total synthesis of penicillin and some of its analogs in the early
1950s, but his methods were not efficient for mass production. Florey
and Chain shared the 1945 Nobel prize in medicine with Fleming for
this work, and, after WWII, Australia was the first country to make
the drug available for civilian use. Penicillin has since become the
most widely-used antibiotic to date, and is still used for many Gram-
positive bacterial infections.