Discovery of Penicillin (1928): Alexander Fleming's Mouldy Plate

In September 1928 the Scottish bacteriologist Alexander Fleming noticed that a mould contaminating one of his culture plates at St Mary’s Hospital in London had killed the bacteria around it. The substance it produced, which he named penicillin, became the first widely used antibiotic. The discovery of penicillin is one of the most famous stories in science, but Fleming’s observation was only the beginning: it took a team at Oxford and an industrial effort in wartime America to turn it into a drug that would save millions of lives.

Background: a world without antibiotics

In the 1920s ordinary infections were often deadly. A scratch, a sore throat, pneumonia or childbirth could lead to blood poisoning that doctors could do little to stop. Germ theory, developed in the late 19th century by scientists such as Louis Pasteur and Robert Koch, had explained the cause of such diseases, and antiseptics could clean wounds, but there was almost nothing that killed bacteria inside the body without harming the patient.

Fleming, born in Ayrshire in 1881, had served in army hospitals in France during the First World War and seen many soldiers die of infected wounds. Back at St Mary’s Hospital Medical School in Paddington, he worked in the inoculation department under Sir Almroth Wright, searching for natural antibacterial substances. In 1921–22 he discovered lysozyme, an enzyme in tears and mucus that destroys some bacteria, though it proved of little medical use.

What happened in September 1928

Fleming was known for a somewhat untidy laboratory. Before going on holiday in the summer of 1928 he left a pile of culture plates of Staphylococcus bacteria on his bench. When he returned on about 3 September, he noticed that one plate had been contaminated by a mould. Around the mould the bacterial colonies had become transparent and were dissolving, while colonies farther away grew normally.

Fleming grew the mould in liquid broth and found that the “mould juice” could kill a wide range of disease-causing bacteria, including those responsible for scarlet fever, pneumonia, meningitis and diphtheria, while appearing harmless to white blood cells. On 7 March 1929 he named the active substance penicillin, after the mould, which was eventually identified as a species of Penicillium. He published his results in the British Journal of Experimental Pathology in 1929.

The contamination itself was a remarkable piece of luck. The mould spore most likely drifted up from a mycology laboratory on the floor below, and a spell of cool weather followed by warmer temperatures appears to have allowed the mould to grow before the bacteria, a sequence later reconstructed by Fleming’s colleague Ronald Hare.

Penicillin was unstable and present in tiny amounts, and Fleming, a bacteriologist rather than a chemist, could not extract and concentrate it. His assistants Stuart Craddock and Frederick Ridley made some progress but could not produce a stable form. Fleming used crude mould juice as a local antiseptic on a few patients and as a laboratory tool for separating bacteria, but he did not carry out the animal experiments that would have shown its power against systemic infections.

During the 1930s attention shifted to another class of drugs: the sulphonamides, introduced by the German chemist Gerhard Domagk in 1935. They were the first effective antibacterial medicines taken internally, and they showed that such drugs were possible. Penicillin remained largely a laboratory curiosity.

The Oxford team

In 1939 Howard Florey, an Australian pathologist and head of the Sir William Dunn School of Pathology at the University of Oxford, and Ernst Chain, a biochemist who had fled Nazi Germany, began a systematic study of natural antibacterial substances. They chose penicillin after Chain read Fleming’s 1929 paper. The biochemist Norman Heatley devised ingenious ways to grow the mould and extract the drug, using improvised equipment including bedpans, milk churns and bathtubs.

On 25 May 1940 the team infected eight mice with lethal streptococci and treated four of them with penicillin. The next morning the treated mice were alive and the untreated ones dead. The results, published in The Lancet in August 1940, showed that penicillin could cure deadly infections inside a living body.

In February 1941 the team treated its first human patient, Albert Alexander, a 43-year-old Oxford police constable with a severe infection that had spread from a scratch. He improved dramatically within days, but the supply ran out, even though penicillin was recovered from his urine and reused, and he died in March. Later patients, mostly children who needed smaller doses, recovered fully.

Mass production in wartime

Wartime Britain lacked the industrial capacity to make penicillin in quantity. In July 1941 Florey and Heatley travelled to the United States, where they were directed to the Department of Agriculture’s Northern Regional Research Laboratory in Peoria, Illinois. Scientists there, including Andrew Moyer, greatly increased yields by growing the mould in corn steep liquor, a by-product of maize processing, and by using deep-tank fermentation instead of shallow trays.

A search for better strains found a highly productive Penicillium chrysogenum on a mouldy cantaloupe from a Peoria market. With support from the US government’s wartime research office, companies including Pfizer, Merck and Squibb built large fermentation plants. Production rose from tiny amounts in 1942 to enough to treat Allied casualties by the Normandy landings of June 1944, and penicillin became available to civilians in the United States in 1945.

Key people

• Alexander Fleming (1881–1955): discovered penicillin’s antibacterial action in 1928; knighted in 1944.
• Howard Florey (1898–1968): led the Oxford team that developed penicillin as a drug; later made a life peer.
• Ernst Chain (1906–1979): biochemist who worked out penicillin’s purification and helped propose its structure.
• Norman Heatley (1911–2004): devised the extraction and production methods that made the Oxford experiments possible.
• Dorothy Hodgkin (1910–1994): used X-ray crystallography to determine penicillin’s molecular structure in 1945.

Consequences

Penicillin transformed medicine. Infections such as pneumonia, syphilis, gonorrhoea, scarlet fever and infected wounds, which had killed or disabled many people, became treatable. Surgery and childbirth became safer, and the drug made possible later advances such as organ transplants and intensive chemotherapy, which depend on controlling infection.

In 1945 Fleming, Florey and Chain shared the Nobel Prize in Physiology or Medicine. Chemists also learned to change the penicillin molecule itself. John Sheehan at the Massachusetts Institute of Technology achieved the first chemical synthesis of penicillin in 1957, and researchers at the British company Beecham isolated its core structure in the late 1950s. This led to semi-synthetic penicillins such as methicillin (1959) and ampicillin (1961), designed to resist bacterial enzymes or to attack a wider range of germs. Strains of Staphylococcus aureus resistant to methicillin, the ancestors of today’s MRSA, were reported in Britain as early as 1961.

Penicillin’s success launched a worldwide search for more antibiotics, such as streptomycin in 1943, and pharmaceutical companies grew into global industries. The period from the 1940s to the 1960s is often called the golden age of antibiotic discovery.

Myths and facts

• Myth: Fleming produced the first penicillin drug. Fleming made the discovery, but the drug was developed by the Oxford team and mass-produced largely in the United States.
• Myth: Fleming’s family saved Winston Churchill, and Churchill’s father paid for Fleming’s education. This popular story has no basis in evidence.
• Myth: penicillin cured Churchill’s pneumonia in 1943. Churchill was treated with a sulphonamide drug, not penicillin, during his illness at the end of 1943.
• Myth: the discovery was pure luck. Chance played a big part, but Fleming’s training and earlier work on lysozyme prepared him to recognise the significance of what he saw.

Legacy

Fleming became a worldwide celebrity, partly because the press found his story of a chance discovery easier to tell than the complex team effort at Oxford. Historians now stress that penicillin was a collective achievement linking a London hospital, a university laboratory and American industry. His restored laboratory at St Mary’s Hospital is now the Alexander Fleming Laboratory Museum.

In his Nobel lecture Fleming warned that misuse of penicillin could make bacteria resistant, and antimicrobial resistance is now one of the most serious threats to global health. Penicillin belongs alongside the discovery of insulin and the Salk polio vaccine among the medical advances that shaped the 20th century.

Timeline

• 1928, c. 3 September: Fleming notices the mould killing bacteria on a culture plate.
• 1929, 7 March: Fleming names the substance penicillin.
• 1929: Fleming publishes his findings in the British Journal of Experimental Pathology.
• 1939: Florey and Chain begin their Oxford research on penicillin.
• 1940, 25 May: The Oxford mouse experiment demonstrates penicillin’s power.
• 1941, February: Albert Alexander becomes the first patient treated by the Oxford team.
• 1941, July: Florey and Heatley travel to the United States to seek production.
• 1944, June: Penicillin is available in quantity for Allied forces at D-Day.
• 1945, December: Fleming, Florey and Chain receive the Nobel Prize.

Why it matters

Penicillin was the first antibiotic to be used widely and opened an era in which bacterial infections could be cured rather than endured. Its story shows how a chance observation becomes a life-saving medicine only through persistent research, collaboration and industrial scale, and Fleming’s own warning about resistance remains urgent today.