Penicillin: How a Mouldy Dish Gave the World Its First Wonder Drug

A World Before Antibiotics

Until the 1940s, a small cut could be deadly. A scratch that became infected, a sore throat caused by streptococcal bacteria, or an infection after childbirth or surgery could spread through the body with nothing to stop it. Doctors could clean wounds, drain pus and hope the patient's immune system won the fight, but they had no reliable way to kill bacteria inside the body. Pneumonia, blood poisoning (sepsis) and infected wounds killed huge numbers of people, including many soldiers in the First World War who survived their injuries only to die from the infections that followed.

Some chemical drugs had appeared before penicillin. Arsenic-based Salvarsan, introduced in 1910, could treat syphilis, and the sulfonamide drugs of the 1930s were a real advance. But they worked against a limited range of germs and could have serious side effects. The medicine that truly opened the age of antibiotics came not from a chemistry lab but from a mould.

What Penicillin Is

Penicillin is not a single substance but a group of related antibiotics. They were first obtained from Penicillium moulds, the same group of fungi that produces the blue-green fuzz on old bread and fruit. Today the main producer is Penicillium chrysogenum, along with the closely related P. rubens. Several species of Penicillium are able to make penicillins naturally.

Chemically, all penicillins share a key feature called the β-lactam ring (beta-lactam ring): a small, tightly strained square of four atoms, three carbons and one nitrogen. This ring is fused to a second ring containing sulfur. The strain in that little square is what makes the molecule so reactive, and, as we will see, it is the secret of how penicillin attacks bacteria. Because of this ring, penicillins belong to the larger family of β-lactam antibiotics, which also includes cephalosporins and carbapenems.

Many natural penicillins have been discovered, but only two purified natural compounds are used in medicine: penicillin G (benzylpenicillin) and penicillin V (phenoxymethylpenicillin). The others used today are semi-synthetic versions, built in the lab on the penicillin core.

The Accidental Discovery

Fleming's Contaminated Plate

The famous story begins in September 1928 at St Mary's Hospital in London. The Scottish bacteriologist Alexander Fleming was studying Staphylococcus bacteria, which cause boils, wound infections and other illnesses. He returned from a summer holiday to find that one of his culture dishes had been contaminated by a mould. Around the mould was a clear zone where the bacteria had been destroyed, while further away the bacterial colonies grew normally.

Fleming realised that the mould was releasing something that killed the bacteria or stopped them from growing. He grew the mould in liquid broth and found that this "mould juice" could stop many kinds of harmful bacteria, including those causing scarlet fever, pneumonia and diphtheria. He named the active substance penicillin and published his findings in 1929.

Why the Discovery Almost Stalled

Fleming had found something remarkable, but he could not turn it into a medicine. Penicillin was produced in tiny amounts, it was chemically unstable, and it broke down quickly. Fleming was not a chemist, and his attempts to purify and concentrate it were unsuccessful. Crude penicillin was tried in a few small experiments on surface infections, but for about a decade penicillin remained mostly a laboratory curiosity.

Fleming was also not the first to notice that moulds can harm bacteria. Several scientists in the 19th century had observed that Penicillium and other moulds could hold back bacterial growth. What made Fleming's work important was that he identified, named and described the substance, and kept the mould alive so that others could later study it.

From Laboratory Curiosity to Lifesaving Medicine

The Oxford Team

The breakthrough came at the University of Oxford in the late 1930s. A team at the Sir William Dunn School of Pathology, led by the Australian pathologist Howard Florey and including the German-born biochemist Ernst Chain and the biochemist Norman Heatley, decided to study natural substances that kill bacteria. They read Fleming's paper and chose penicillin.

Purifying penicillin was extremely difficult. Heatley invented clever methods to extract it, transferring it between liquids of different acidity so that it could be separated from the broth and concentrated. Because the Second World War had begun and equipment was scarce, the team improvised: they grew the mould in hundreds of vessels, including bedpans and specially made ceramic containers, and hired young women, later nicknamed the "penicillin girls", to tend the cultures.

The Mouse Experiment and the First Patient

In May 1940 the team carried out a decisive experiment. They infected eight mice with a deadly dose of streptococcal bacteria. Four of the mice were then given penicillin and four were not. By the next morning all four untreated mice were dead, while the treated mice were still alive. Penicillin clearly worked inside a living body.

In early 1941 the team treated their first human patient, an Oxford police constable named Albert Alexander, who had a severe infection of his face and scalp. Within days of receiving penicillin he began to improve dramatically. But the team had so little of the drug that they even recovered penicillin from his urine to use again. When the supply ran out, the infection returned and he died. His case proved two things at once: penicillin could save lives, and it was needed in far larger quantities.

Mass Production and the Second World War

Britain, under wartime pressure, could not produce penicillin on a large scale, so in 1941 Florey and Heatley travelled to the United States to seek help. They worked with scientists at a government agricultural laboratory in Peoria, Illinois, where researchers had experience with growing microbes in large amounts.

Three discoveries transformed production:

• Corn steep liquor, a by-product of processing maize, turned out to be an excellent food for the mould and greatly increased the amount of penicillin it made.
• Deep-tank fermentation allowed the mould to grow submerged in huge tanks of stirred, aerated liquid, instead of as a thin layer on the surface of flasks and trays.
• A better mould was found on a mouldy cantaloupe melon bought at a Peoria market. Its strain of Penicillium chrysogenum produced far more penicillin than Fleming's original mould, and mutated descendants of it were developed into even more productive strains.

American pharmaceutical companies then scaled up manufacture with government support. Production rose so quickly that millions of doses were available for the Allied landings in Normandy in June 1944. Penicillin saved the lives of many wounded soldiers and greatly reduced deaths from infected wounds and pneumonia. After the war it became widely available to civilians around the world.

In 1945 Fleming, Florey and Chain shared the Nobel Prize in Physiology or Medicine for the discovery of penicillin and its curative effect in various infectious diseases. Norman Heatley, whose methods had made purification possible, was not included, although Oxford later honoured his contribution.

How Penicillin Kills Bacteria

Attacking the Cell Wall

Bacteria are surrounded by a tough outer layer called the cell wall. It is made of a mesh-like material called peptidoglycan, long chains of sugars linked together by short bridges of amino acids. This mesh works like a corset: the inside of a bacterial cell is under high pressure, and the wall stops the cell from swelling and bursting.

As a bacterium grows and divides, it must keep building new wall. Special enzymes, called penicillin-binding proteins, create the cross-links that hold the mesh together. Penicillin's β-lactam ring looks similar to the natural building block these enzymes grab. The enzyme latches onto penicillin instead, the strained ring springs open, and the antibiotic becomes permanently stuck to the enzyme, putting it out of action.

Without working cross-linking enzymes, the bacterium builds a weak, faulty wall. As water pushes in, the cell swells and bursts. This is why penicillin works best against bacteria that are actively growing and dividing.

Why It Does Not Harm Human Cells

Human and animal cells do not have a peptidoglycan cell wall at all. Their outer boundary is a flexible membrane. Because penicillin's target simply does not exist in our cells, it can kill bacteria while leaving the body's own cells largely unharmed. This idea of selective toxicity, hitting something the germ has but we lack, is one of the most important principles in medicine.

Which Bacteria It Affects

Penicillin G works especially well against Gram-positive bacteria such as streptococci, whose thick peptidoglycan wall is exposed on the outside. Gram-negative bacteria, such as E. coli, have an extra outer membrane that blocks many penicillins from reaching their target. Penicillin has no effect on viruses, so it cannot cure colds or flu.

The Penicillin Family Grows

Natural penicillin had limits. Penicillin G is destroyed by stomach acid, so it must be given by injection. Penicillin V is more resistant to acid and can be taken as tablets, which made treatment much easier.

The structure of penicillin was worked out by the British chemist Dorothy Crowfoot Hodgkin, who used X-ray crystallography during the war years to show the exact arrangement of its atoms and confirm the β-lactam ring. She later received the 1964 Nobel Prize in Chemistry for her work on the structures of important biological molecules. In 1957 the American chemist John Sheehan achieved the first complete chemical synthesis of penicillin, although making it this way was never as practical as fermentation.

A key step came in the late 1950s, when British researchers at the Beecham company isolated the core of the penicillin molecule, known as 6-APA. Chemists could now attach different side chains to this core and design new penicillins with better properties. The results included:

• Methicillin, made to resist enzymes that some bacteria use to destroy penicillin.
• Ampicillin, which reached a wider range of bacteria, including some Gram-negative ones.
• Amoxicillin, introduced in the early 1970s, absorbed well when swallowed and today one of the most commonly prescribed antibiotics in the world.

Penicillin in Medicine Today

More than 80 years after its first use, penicillin is still an essential medicine. It is used to treat strep throat, some types of pneumonia, skin infections, syphilis and several other bacterial diseases, and to prevent rheumatic fever in people at risk. Penicillins appear on the World Health Organization's Model List of Essential Medicines, which names the drugs every health system should have.

Like all medicines, penicillin can cause side effects. The best known is allergy, which in rare cases can be severe. Interestingly, many people who were told as children that they are allergic to penicillin turn out not to be when properly tested, often because a rash caused by an illness was mistaken for a drug reaction. Doctors now encourage allergy testing, because avoiding penicillin unnecessarily can mean using less suitable antibiotics.

The Rise of Resistance

Bacteria evolve, and penicillin's success created strong pressure for them to survive it. The main defence is an enzyme called β-lactamase (or penicillinase), which cuts open the β-lactam ring and makes the antibiotic useless. Remarkably, Ernst Chain and his colleague Edward Abraham described such an enzyme in bacteria in 1940, before penicillin was in general use. Other bacteria change their penicillin-binding proteins so that the drug can no longer grip them.

Within a few years of penicillin becoming widely available, resistant strains of Staphylococcus aureus were spreading in hospitals. Later came MRSA (methicillin-resistant Staphylococcus aureus), which resists methicillin and most other penicillins. To fight back, doctors sometimes combine a penicillin with a β-lactamase inhibitor such as clavulanic acid, which protects the antibiotic from being broken down; amoxicillin with clavulanic acid is a common example.

Fleming himself foresaw this danger. In his Nobel lecture in 1945 he warned that taking too little of the drug could allow bacteria to become resistant. His warning is still relevant: using antibiotics when they are not needed, such as for viral infections, or not taking them as prescribed, helps resistant bacteria spread. Antibiotic resistance is now considered one of the biggest threats to global health.

Lesser-Known Facts

• Fleming's laboratory at St Mary's Hospital has been preserved and is now a small museum.
• In the early days penicillin was so precious that it was recovered from patients' urine, purified and given again.
• The cantaloupe mould from Peoria was found by a laboratory assistant, Mary Hunt, who searched markets for mouldy produce and became known as "Mouldy Mary".
• Industrial strains of Penicillium today produce many times more penicillin than Fleming's original mould, thanks to decades of selection and improvement.
• Penicillin's success inspired a worldwide search for other antibiotics from soil microbes and fungi, leading to streptomycin, tetracyclines and many more in the following decades.

Why Penicillin Matters

Penicillin changed what medicine could do. Infections that once killed quickly became treatable, and operations, cancer treatments, organ transplants and the care of premature babies all became safer because doctors could control bacterial infection. Its story also shows how science really works: an accidental observation, years of patient effort by a team of chemists and doctors, international cooperation and industrial engineering all had to come together. And the spread of resistance reminds us that this gift must be used wisely, so that penicillin and the antibiotics that followed it keep working for future generations.