History of Penicillin Production: Bioreactors, Strains, and Medium

This essay provides a comprehensive overview of the history of penicillin production, tracing its development from the initial discovery by Alexander Fleming to the advancements made at Oxford University and the Northern Regional Research Laboratory (NRRL). The essay details the critical role of Ernest Chain and Howard Florey in transforming penicillin into a life-saving drug, highlighting the challenges faced in mass production and the subsequent collaboration with the American pharmaceutical industry. Furthermore, it explores the improvements in bioreactor configuration, the development of high-yield strains through submerged culture fermentation and strain screening, and the medium improvements that led to increased penicillin yields. The discussion covers the impact of these advancements on the global availability and use of penicillin as an essential antibiotic, emphasizing the significance of bioprocessing and biotechnology in modern drug manufacturing.

THE HISTORY OF PENICILLIN 1
THE HISTORY OF PENICILLIN
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Introduction
Penicillin infers to antibacterial drugs that inhibits bacterial growth. Penicillium fungi are
the primary source of penicillin which is administered either through injection or orally.
Furthermore, antibiotics are composites produced by fungi and bacteria which can inhibit the
competing bacteriological species (Macy, and Contreras, 2014 pp.790-796). It is now clear why
the ancient Egyptians applied mold bread to infected wounds. Typically, penicillin is the first
drugs of this nature that physicians used to treat wounds. Recent studies have shown that the
discovery of penicillin has dramatically changed the face of medicine because the drug has saved
millions of lives (Silverman, and Holladay, 2014). The era of antibiotics began in the 1940s the
time when penicillin was introduced. The discovery of the antibacterial drug (penicillin) is
considered to be the most significant advancement in the field of therapeutic medicine. Penicillin
drug is used worldwide to treat infections and diseases.
Moreover, the primary function of penicillin is used to fight bacteria by destroying its
walls. Typically, they do this by directly attacking peptidoglycans which plays a critical role in
the structure of a bacterial cell. Penicillin drug is essential because it is used to treat a wide range
of inclined bacteria, such as gonorrhea, ear infections (otitis media), pneumonia, urinary tract
and skin infections (Macy, 2014 p. 476). Despite, the benefits of penicillin it still has some side
effects such as abdominal pain, test pervasion, and diarrhea. The paper seeks to discuss the
history of penicillin. Also, the discussion will include the medium improvements, improvements
in bioreactors and development of high yield strains.
History of Penicillin

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According to Alharbi, et al., 2014 pp. 289-292) penicillin discovery is one of the most
significant advancements in the field of medicine that saved many lives across the globe, and
ironically enough the drug was discovered accidentally. However, many ancient societies
including those in India, Egypt, and Greece revealed the critical use of plants and fungi
components in treating infections. It is clear that the mode of treatment worked because many
species of mold, obviously secretes antibiotics components that inhibit the growth of bacteria.
Nevertheless, the ancient physicians failed to identify the active elements of this organisms.
Recent studies have shown that soldiers in Seri Lanka used to apply a poultice of the cake to treat
gun wounds (Fishovitz, Hermoso, Chang, and Mobashery, 2014 pp. 572-577). Also, in Poland,
the ancient physicians mixed spider webs and wet bread to treat wounds as the mixture contained
components of fungal spores.
Moreover, the modern history of penicillin began in the United Kingdom in the early
1870s. Sir John Scott Burdon-Sanderson noticed that artistic fluids covered with mold would
inhibit bacterial growth. Sanderson’s discovery encouraged Joseph Lister who did further
research, and he discovered that urine sample contaminated with mold also did not allow the
growth of bacteria. In 1897 Ernest Duchesne discovered the healing nature of Penicillium
glaucum mold which treated typhoid and infected guinea pigs (Ventola, 2015 p. 277). He based
his assumption on the discovery made by the Arabs as they used the mold to treat wounds on
heroes. However, Ernest did not mention if the mold contains any form of antibacterial
substances, he only proposed that the mold somehow protected the animal. Also, his claim that
mold cure typhoid is unknown because the isolated penicillin discovered by Fleming did not cure
the illness. In 1982 there was a breakthrough in the field of medicine as Alexander Fleming was
able to isolate penicillin.

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Penicillin was discovered in 1928 by a Scottish bacteriologist called Alexander Fleming.
Sir Alexander Fleming was a professor at St. Mary's Hospital in London. Returning of Alexander
from his holiday on September third, 1982, he began to sort petri dish that he had left filed with
Staphylococcus aureus bacterium. The bacterium was left uncovered for several days. Typically,
the bacterium causes abscesses, boil, and sore throats. During the process of sorting the dishes,
he noticed something uncommon in one of the recipes (Singh, 2014 pp. 3686-3689). The petri
dish was dotted with colonies where mold was growing on one side. The professor was about to
throw the petri dish but he noticed that the mold was dissolving the Staphylococcus aureus
bacterium away. The area around the mold was identified as a rare strain of Penicillium notatum.
The Penicillium notatum area appeared to be clear this is because the mold had secreted a
component that impedes bacterial growth.
Alexander Fleming found out that his “mold juice” could destroy harmful bacteria such
as diphtheria bacillus, streptococcus, and meningococcus. Fleming then delegated the hard task
to his assistances Frederick Ridley and Stuart Craddock to isolate pure penicillin from the mold
juice. However, the process of isolation was unfruitful because they were only able to produce
solutions to work with and it proved to be unstable. In June 1929 Fleming published his work of
penicillin’s benefits in the British Journal of Experimental psychology (Sheingold, and Hahn,
2014 pp. 18-22). The primary application at this stage was to isolate penicillin from mold juice.
Indeed, it was an applied benefit to the bacteriologist, which kept the advancement in penicillin
going. Moreover, Alexander Fleming grew, and he was able to distribute his original work which
was ultimately identified as Penicillium notatum. However, much Fleming made a breakthrough
in the field of medicine he was unable to make a stable form of penicillin for mass production.
Penicillin Research at Oxford University

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Ernest Chain and Howard Florey together with their colleagues at the University of
Oxford made a significant move in the advancement of penicillin as they were able to turn
penicillin into a lifesaving drug. The primary goal of Howard Florey together with his colleagues
was to produce a stable and quality form of penicillin. Their work on the chemistry and
purification of penicillin began in 1939 (Walia, Borle, Mehendiratta, and Yadav, 2014 pp. 16-21)
Oxford team required a massive amount of mold to experiment on both animal and humans.
Therefore, they invented ways of producing mold; for example, they used cultural vessels such
as food tins, milk charm, bedpans, and baths. Later, they designed a fermentation vessel which
made it easy to renew the broth and remove the mold. Also, due to the increased workload, some
girls were employed to look after the fermentation process. It is clear that the Oxford university
laboratory was being turned in to penicillin factory.
Furthermore, a biochemist called Norman Heatley made a significant step as he was able
to extract a massive amount of penicillin. Norman used a countercurrent system to extract
penicillin. Also, another biochemist called Edward Abraham was employed to help in the
production penicillin (Liu, et al., 2015 pp. 695-703). Edward used alumina column
chromatography technique to purify penicillin before a medical test.
Moreover, Chain and Edward Abraham in 1940 were the first people to discover that
penicillin has antibiotics resistance. Typically, the antibiotic resistance on penicillin was known
as an E. coli strain which produces penicillinase enzyme. The enzyme was responsible for
breaking down penicillin and entirely refuting its bacterial effects. The same year Florey carried
out a critical experiment on mice (Nissen, and Wynn, 2014 p. 264). His research revealed that
penicillin has a vital role in shielding mice against infections from lethal Streptococci. In 1941 a
police officer called Albert Alexander was the first receiver of the Oxford penicillin. Albert

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scratched his mouth while he was trimming roses. The injury was infected with massive
abscesses which is a life-threatening condition. The infection affected both his lungs, eyes, and
face. Penicillin was administered through injection, after a few days, Albert made an
extraordinary recovery. However, Alexander died because there was no enough drug to treat the
condition. It was the greatest achievement in medicines as there was a plan to make the drug
available for British troops (Bush, K., 2004 pp. 10-17). Nevertheless, war conditions at that time
made it difficult for industrial production of penicillin.
Florey realized that massive production of penicillin was out of the question in Britain
because the chemical industries were preoccupied with war activities. Therefore, Florey and his
colleagues traveled to the United States to engage with the American pharmaceutical industry in
a determination to produce penicillin in large scale. There was a need to produce penicillin in
large scale considering its benefits across the globe (Patridge, E., Gareiss, P., Kinch, M.S. and
Hoyer, D., 2016 pp. 204-2017). Northern Regional Research Laboratory (NRRL) played a
critical role in a massive production of penicillin because the company had expertise in
fermentation division.
Increasing the Yield of Penicillin
The Northern Regional Research Laboratory agreed to increase penicillin yield. The
project was under Robert Coghill who was the director of fomentation division. Moreover,
Andrew Moyer discovers that he could increase the yield of penicillin by replacing lactose for
the sucrose that was used by the Oxford University team in their experiment (Josephson, K.,
Ricardo, and Szostak, 2014 pp. 388-399). Later, Moyer made a significant discovery that the
adding of corn-steep liquor to the medium dramatically increases the yield of penicillin.

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Furthermore, it was revealed that the Oxford procedure of growing the mold was
ineffective. Therefore, the NRRL came up with submerged culture fermentation process where
the mold is grown in a large tank. It was found that the Florey’s Penicillium culture only
produced traces of penicillin when they are presented in submerged culture process. The staffs of
Northern Regional Research Laboratory (NRRL) under the supervision of Kenneth Raper
screened several Penicillium strains, and they found one strain that produces a desirable yield of
penicillin in submerged culture (Butler, and Newman, 2015 pp 1-44). The most productive
penicillin producing strain was found in a moldy cantaloupe. At Carnegie, Institution X-ray was
used to produce more productive mutant of cantaloupe strain. Also, it was discovered that when
the strain was exposed to ultraviolent radiation its productivity increased. Recent studies have
shown that standard strain development has been the backbone of high yield production of
penicillin (Genilloud, 2014 pp. 173-188). Typically, one of the essential phenomena in high
yielding penicillium strains is the intensification of the penicillin gene.
Improvements
Recent studies have shown that penicillin and its byproducts are used globally as
antibiotics by both animals and human beings. The past method of penicillin production involves
a batch of reactors that are operated in parallel so that it can withstand a continuous production
of penicillin. Bioprocessing is a complex process that encompasses production of chemicals,
medicines, and biofuels. Typically, the method uses a living organism to produce final products.
Earnest Chain and his counterpart Howard Florey came up with ways of increasing the amounts
of the drugs that were produced. There has been an improvement in bioreactor configuration
over time in the production of penicillin.

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First, a bioreactor is merely an industrial vat used in the process of fermentation of which
various biochemical processes and reaction take place in it. In making up of drugs such as
penicillin, bioreactors are vital and are necessarily required. The bioreactors are specially
designed in a manner that is appropriate for the bioprocesses that take place in them. In the
manufacture of penicillin, various improvements have been made on the mechanical bio
processor systems. There has been a thrust to improve the desired metabolite over time according
to Penesyan, Gillings, and Paulsen, (2015 pp. 5286-5298). Furthermore, in the bioreactors of
penicillin, there has been an increase in microbial production to increased levels. This has helped
increase immensely the amount of penicillin that is being produced all over the world.
There has also been an improvement in the biotechnology used in the production of
penicillin. Mechanical parts that are more resistant to natural agents of wear and tear such as rust
are now being used to make up the mechanical parts of penicillin production plant machines
(Lee, Joory, and Moiemen, 2014 p. 169). Additionally, there has been an improvement in designs
to increase the efficiency of the production plants. This ensures that they are more energy
efficient and can allow for a relatively large amount of mass penicillin transfer compared to
ancient times (Lobanovska, and Pilla, 2017 p. 135).
Genetic and cell manipulation has also been done over time to allow various cell biomass
to grow much better and sometimes even produce different drugs and commodities from
penicillin (June et al., 2014, pp. 333-341). The new systems of production allow for an increase
in the supply of nutrients used in the production as well as cater to dynamics in magnification.
Metabolism among many others in the process of improving penicillin production.
Furthermore, the mechanical bio processor systems of penicillin have been improved
with the production of micro bioreactors. They are not only of low cost but also have helped

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improve the process of optimization and strain improvement in the production of penicillin
(Aldeghi, Malhotra, Selwood, and Chan, 2014 pp. 450-461). Additionally, plant cell factories
have been built to synthesize extensive metabolic activities to fasten the process of production of
penicillin. By this, various metabolically engineered bacteria have been made such as the lactic
acid bacteria that assist in the metabolism of penicillin.
Genomic engineering has also been linked to the development of high yields strains in
penicillin production (Liu, Zhang, Bing, and Shangguan, 2014 pp.2289-2296). With concepts
such as genomic sequencing and gene clustering, there has been a diverse increase in the
varieties of products found from metabolism of penicillin. Genomic sequencing Involves
checking at the DNA sequencing to improve on it by minor adjustments. Gene clustering, on the
other hand, is about grouping up genes together to come up with an improved product (Paul et
al., 2014). The two have been a significant medium of improvement in penicillin production.
Conclusion
Penicillium fungi are the primary source of penicillin which is administered either
through injection or orally. Alexander Fleming discovered penicillin and there were unknown
methods of increasing the production of the drug until later on when scientist such as Earnest
Chain and his counterpart Howard Florey came up with ways of increasing the amounts of the
drugs that were produced. There has been an improvement in bioreactor configuration over time
in the production of penicillin. Penicillin and its byproducts are used globally as antibiotics by
both animals and human beings. The recent method of penicillin production involves a batch of
reactors that are operated in parallel so that it can withstand a continuous production of
penicillin. The most productive penicillin producing strain was found in a moldy cantaloupe. At
Carnegie, Institution X-ray was used to produce more productive mutant of cantaloupe strain.

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Also, it was discovered that when the strain was exposed to ultraviolet radiation its productivity
increased. The mechanical bioprocessor systems of penicillin have been improved with the
production of micro bioreactors. They are not only of low cost but also have helped develop the
process of optimization and strain improvement in the production of penicillin.

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