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How was penicillin developed?

Published: 23 February 2021

Before antibiotics, a relatively minor infection could prove incurable or even deadly. Everything from paper cuts to childbirth had the potential to kill through bacterial infection.

The accidental discovery of a mouldy petri-dish in 1928 kickstarted a 20-year long journey to develop the world’s first mass produced drug that could clear a bacterial infection; penicillin. But why did it take so long?

The Accidental Discovery: Fleming’s Lab, St. Mary's Hospital, London. 1928 to 1929 

In 1928 Dr Alexander Fleming returned from a holiday to find mould growing on a Petri dish of Staphylococcus bacteria. He noticed the mould seemed to be preventing the bacteria around it from growing. He soon identified that the mould produced a self-defence chemical that could kill bacteria. He named the substance penicillin.   

A sample of penicillium mould, gifted by Alexander Fleming to a colleague at St Marys Hospital, London, 1935
Science Museum Group Collection More information about A sample of penicillium mould, gifted by Alexander Fleming to a colleague at St Marys Hospital, London, 1935

Fleming published his findings and presented his discovery to the Medical Research Club. To his surprise, his peers showed little interest in his work.

Undeterred, he enlisted the help of several chemists, all leading experts in their fields, to help purify penicillin from the mould. None were successful.  Professor Harold Raistrick, a Biochemist and expert in fungal substances enlisted by Fleming, declared "the production of penicillin for therapeutic purposes...almost impossible.” 

Penicillin was labelled a laboratory curiosity and Fleming gave up attempts to purify it.

Curious Mould to Wonder Drug 

Nearly ten years later in 1937, while investigating microorganisms and the substances they produced, Howard Florey and Ernst Chain uncovered Fleming’s research and assembled a team of scientists to work solely on the 'Penicillin Project'.

Personality clashes between senior members of the team resulted in heated arguments over how to carry out the research. The ongoing disagreements within the lab, as well as the complexities and scientific challenges of the project, meant the team struggled immensely to purify penicillin from its original mould.   

Florey, Chain and members of the Oxford penicillin team
Florey, Chain and members of the Oxford penicillin team

After three years of trial and error, they developed a successful but painfully inefficient process that produced pure penicillin. The team finally had enough penicillin to start animal trials. In 1940, eight mice were infected with deadly streptococci bacteria. Only the four also given penicillin survived.

The paper they published detailing the experiment gained immediate interest, but the team were now severely limited by production. Gallons of mould broth was required to produce just a fingernail of penicillin. The team resorted to using bedpans, milk churns, food tins and even bathtubs to store the broth. 

Science Museum Group Collection More information

Eventually, special fermentation vessels were developed to hold the liquid.

The preferred fermentation vessel that would be used until mass production deep tanks fermenters, developed in the States, took over.
Science Museum Group Collection More information about The preferred fermentation vessel that would be used until mass production deep tanks fermenters, developed in the States, took over.

With penicillin now in successful albeit slow production, the Oxford laboratory had now become a penicillin factory. Six women, known as the ‘Penicillin Girls’ were employed to tend to the fermenting broth and ‘farm’ a few precious milligrams of penicillin from it every week.

The ‘Penicillin Girls’tending the fermenting broth that produced penicillin
Two of the six ‘Penicillin girls’ that included: Ruth Callow, Claire Inayat, Betty Cooke, Peggy Gardner, Megan Lancaster and Patricia McKegney

In 1941, the consequences of the teams’ production problems and shortage of penicillin became apparent with the first human trial of penicillin. 

Albert Alexander, a 43-year-old policeman, had developed a life-threatening infection from a cut.  He initially showed signs of recovery but the supply of penicillin quickly ran out and Albert’s infection returned. He died five days later.

The team had to turn to somewhat unpleasant measures to bolster their meagre supplies.  Around 80% of a dose of penicillin is excreted from our bodies in our urine and can extracted and recycled. Dr. Ethel Florey, a supervisor for the clinical trials, was regularly observed on the ’P-Patrol’, cycling to patients to collect their urine.

One of the earliest penicillin samples, believed to have been isolated from the urine of a patient given the antibiotic.
Science Museum, London|Sir William Dunn School of Pathology, Oxford More information about One of the earliest penicillin samples, believed to have been isolated from the urine of a patient given the antibiotic.

With their growing success the Oxford team approached pharmaceutical companies to manufacture penicillin. However, with the Second World War in full swing, British industry was not capable of developing a new mass production process, so the team started to look elsewhere.

Scaling up in USA: Mass production, Peoria, Illinois, 1941  

In June 1941 Florey decided to take penicillin to the US in hope of finding a way to scale up production.   

In Peoria, Illinois, a new team was set up in the Department of Agriculture’s research laboratory. They utilised their expertise in fermentation and designed new techniques using deep fermentation tanks to make the purification of penicillin as efficient as possible.  

The lab in Peoria had an abundance of corn-steep liquor, a by-product of corn starch. They discovered that when added to the mould broth, the yield of penicillin increased exponentially.  The high concentration of sugars, amino acids and nitrogen provided an excellent environment for mould fermentation.  
  
They started a global search for strains of mould with higher percentages of penicillin. Soil samples were sent in from around the world. But the solution was found closer to home. Mary Hunt, an Assistant at the Peoria lab, found a rotting cantaloupe melon at a local market. The mould produced six times more penicillin than Fleming’s original strain.   

Science Museum, London|Sir William Dunn School of Pathology, Oxford More information

US Pharmaceutical companies were initially reluctant to commit to large scale penicillin production. However, by the end of 1941 the US joined the Second World War and demand for penicillin rocketed. By 1943, the US had sufficient penicillin stocks to satisfy the demands of the Armed Forces of the United States, as well as their Allies.  

Wartime advertisements for penicillin
Left: Around 20 different labs in the US were producing penicillin  for the war effort, including Schenley Laboratories. Right: Pfizer played one of the biggest roles in the mass production of penicillin

Antibiotics today

In 1946 penicillin became available for the first time in the UK for public use, it transformed medicine worldwide and ushered in the age of antibiotics.

But bacteria have evolved to become resistant to the original penicillin and many other antibiotics. Scientists are now in a race to find and develop new antibiotics.