Penicillin

Initial Discovery – All by Accident 

It has been almost 100 years since the discovery of penicillin and, to this day, its profound impact in medicine and the fight against diseases is indisputable. According to British hematologist Gwyn Macfarlane, the discovery of penicillin was a “series of chance events of almost unbelievable improbability.”[1]

In 1928, Alexander Fleming, a Scottish physician and microbiologist at St. Mary’s Hospital in London, returned to his laboratory after being away on holiday to find that one of his staphylococcus bacteria cultures had been overgrown by a fungus in the petri dish. Rumor has it that he was quite disorganized and messy. What’s more, he noticed that the staphylococcus colonies close to the fungus had died, whereas the ones further away had survived. 

Fleming isolated the mold and, upon examination, identified that it belonged to the Penicillium genus, hence the name penicillin. Fleming determined that penicillin had an anti-bacterial effect on staphylococci and other gram-positive bacteria and published his findings in 1929.

Isolation of Purified Penicillin

While Alexander Fleming made the monumental discovery of penicillin in 1928, he was unsuccessful in his efforts to purify the unstable compound from the extract of the mold, and, for about a decade, no progress was made. In the hope of making headway, Fleming sent samples of his penicillium mold to anyone who was interested; one of those samples had been sent to, and saved at, Oxford University. 

In 1939, pathologist Howard Florey, fungal expert Norman Heatley, and biochemist Ernst Chain successfully purified penicillin and began experiments on mice. The results were so astonishing that, in 1940, the researchers published their findings in The Lancet – one of the world’s oldest and best-known general medical journals. The published article explained how experimental use of penicillin had been potent enough to treat mice that had been infected with staphylococcus aureus, streptococcus pyogenes, and Clostridium septique[2]

In 1945, Alexander Fleming, Howard Florey and Ernst Chain were awarded the Nobel Prize for Medicine and Physiology.

First use of Penicillin in Humans

The researchers at Oxford University – known as the Oxford team – had been successful in their penicillin experiments on mice and had purified enough amounts of the drug to start testing its clinical effectiveness in humans. 

The first patient to receive penicillin treatment was an Oxford policeman in 1941, who was exhibiting signs of a serious infection with abscesses all over his body. His improvement over 24hrs was remarkable, but the supplies of purified penicillin ran out before he had a chance to fully recover, and he died a few weeks later. 

However, other patients with less advanced infections received the drug and recovered successfully. The Oxford team quickly realized that they had to find a way to mass produce penicillin. As the British pharmaceutical industry was fully engaged in the WWII effort, Florey and his colleagues decided to turn to the US for assistance.

US Involvement in Penicillin’s Mass Production

The Oxford team of researchers that had been successful in isolating purified penicillin from mold decided to turn to the U.S. for help in finding a way to mass-produce the drug. As the USA still wasn’t involved in WWII, Florey and Heatley were hopeful they would be able to interest the American pharmaceutical industry in assisting with the production of penicillin on a large scale. 

Their evidence on the drug’s ability to treat infection was so substantial that the U.S. Office of Scientific Research and Development agreed to participate in the increased production of penicillin. In December 1941, Japan attacked Pearl Harbor and the United States entered WWII, making the need for large supplies of penicillin even more urgent, and the USA took over all production of the drug. 

By 1943, due to unprecedented collaboration between Britain and the USA, enough quantities of penicillin were being produced to satisfy the demands of the Allied Armed Forces[3], saving thousands of soldiers’ lives.

The Antibiotic Era

Antibiotics are classified in 2 categories: those that act as bactericidal agents, causing bacteria cell death, and those that act as bacteriostatic agents, restricting growth and reproduction of bacteria[4]. Penicillin and penicillin-derived antibiotics such as amoxicillin, belong to the first category and treat infections such as tonsillitis and bacterial pneumonia. Antibiotics such as erythromycin belong in the second category and prevent the further growth of bacterial infections, including acne and chlamydia. 

Alexander Fleming’s discovery of penicillin in 1928 marked the beginning of the antibiotic era and changed the medical landscape forever. According to Stephen Whitehead, chief executive of the Association of British Pharmaceutical Industry, “without antibiotics, modern medicine as we know it would be unrecognizable.”[5]

The discovery of penicillin also changed the process of drug discovery and transformed the pharmaceutical industry. The so-called ‘golden era’ of antibiotics lasted until the late 1950s, during which most of the antibiotic classes we use today were discovered and introduced to the market.

Antibiotics & Their Effect on the Gut Microbiome 

The human gut microbiome is “the collection of all microbes, such as bacteria, fungi, viruses, and their genes, that naturally live on our bodies and inside us.”[6] These microbes protect us against pathogens that cause disease and influence how our immune system develops. As a result, changes in the gut microbiome can affect how the body responds to disease.

Studies have shown that antibiotics can cause a significant decrease in the bacterial diversity found in the gut and alter the microbiome causing gut dysbiosis, i.e. an imbalance of the bacteria and microbes in the gut. This can lead to a multitude of complications, from infections such as Clostridioides difficile, which causes diarrhea, to the dysregulation of immune responses and, thus, bringing on new conditions including asthma and food intolerances[7].

Antibiotic Resistance

In 1940 Edward Abraham and Ernst Chain reported that an E.coli strain was able to inactivate penicillin by producing an active enzyme called penicillinase[8], while, in 1945, Alexander Fleming predicted that the high demand for antibiotics would introduce an “era of abuse.” Once penicillin became available by prescription, the antibiotic started to be overused and Fleming’s prediction became a reality[9]

Since then, studies have proved the correlation between increased antibiotic use and the emergence of resistance, with each new generation of antibiotics following the same trend. To survive, germs that cause infections develop defense strategies against antibiotics called resistance mechanisms[10]. These resistance mechanisms include changing or even destroying the antibiotic with enzymes that break down the drug. As a result, diseases are becoming harder or even impossible to treat.

The Need for New Antibiotics

Antibiotic resistance is also known as antimicrobial resistance or AMR. The World Health Organization has declared that AMR is one of the top 10 global public health threats facing humanity today[11], with certain infections such as pneumonia and TB becoming increasingly harder to treat. 

According to The World Health Organization, new antibiotics are urgently needed but the clinical pipeline is limited; only 32 antibiotics addressing The World Health Organization’s list of priority pathogens were identified in clinical development in 2019, of which only 6 were classified as innovative[12]. However, if current practices in how antibiotics are prescribed and used don’t improve, any new drugs developed will also eventually become ineffective.

Research into the human gut microbiome – the community of helpful bacteria that reside within our digestive systems – has also begun to show the dangers of overuse of antibiotics. In particular, over prescription of ‘broad-spectrum’ antibiotics that indiscriminately eradicate both bad and good bacteria within us.

Sources

[1] Macfarlane G. Alexander Fleming: the man and the myth. Cambridge (MA): Harvard University Press, 1984.

[2] Chain E, Florey HW, Gardner NG, Heatley NG, Jennings MA, Orr-Ewing J, et al. Penicillin as a chemotherapeutic agent. 1940: Lancet, 236(6104),pp. 226-228.

[3] American Chemical Society. International chemical landmark. Discovery and development of penicillin [cited 1999 Nov 19]. https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html

[4] Compound Interest. A brief Overview of Classes of Antibiotics [cited 8 September 2014]. https://www.compoundchem.com/2014/09/08/antibiotics/

[5] Christian Millman. 10 Breakthrough Moments in Medicine. Discover Magazine, [cited 23 October 2019]. https://www.discovermagazine.com/health/10-breakthrough-moments-in-medicine

[6] National Institute of Environmental Health Sciences. Microbiome. https://www.niehs.nih.gov/health/topics/science/microbiome/index.cfm

[7] National Library of Medicine. Effects of Antibiotics upon the Gut Microbiome: A Review of the Literature. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696078/

[8] Mariya Lobanovska and Giulia Pilla. Penicillin’s Discovery and Antibiotic Resistance: Lessons for the Future? National Centre for Biotechnology Information [cited 29 March 2017]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369031/

[9] Bartlett JG, Gilbert DN, Spellberg B. Seven ways to preserve the miracle of antibiotics. Clinical Infectious Diseases. 2013;56(10), pp.1445–1450.

[10] Centres for Disease Control and Prevention. How Antibiotic Resistance Happens. https://www.cdc.gov/drugresistance/about/how-resistance-happens.html

[11] World Health Organization. Antimicrobial Resistance. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance

 [12] Ibid.

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