The Discovery of Penicillin

The Messy Lab

In September 1928, Alexander Fleming returned to his laboratory at St Mary's Hospital in London after a two-week holiday. He was not a tidy man. Before leaving, he had stacked several petri dishes containing Staphylococcus bacteria cultures on his bench, intending to clean them when he got back.

When he picked up one of the dishes, he noticed something strange. A blob of blue-green mold — later identified as Penicillium notatum — had contaminated the dish. This happened all the time in laboratories. What was unusual was what had happened around the mold.

The bacteria were gone. In a perfect circle around the mold colony, the Staphylococcus had dissolved. The mold was producing something that killed bacteria.

"That's funny," Fleming said — the most understated reaction in the history of medicine.

He grew more of the mold, extracted the liquid it produced, and tested it against a range of bacteria. It killed Staphylococcus, Streptococcus, and the bacteria that cause diphtheria, scarlet fever, and pneumonia. He called the substance penicillin.

Then he published his results. And nothing happened.

The Fifteen-Year Gap

Fleming's 1929 paper described penicillin's antibacterial properties clearly. But he couldn't figure out how to purify it. The mold produced penicillin in tiny quantities, mixed with a soup of other chemicals. Every attempt to concentrate it destroyed the active molecule. Fleming concluded that penicillin was too unstable to be useful as a medicine.

For fifteen years, penicillin sat in the scientific literature — a curiosity that everyone knew about and nobody could use.

Then, in 1939, World War II began. Suddenly, the need for antibacterial drugs became urgent. Soldiers were dying not from bullets but from infected wounds — a cut that would heal in peacetime became fatal when bacteria invaded, and the body's immune system couldn't keep up.

At Oxford University, two scientists — the Australian pathologist Howard Florey and the German-British biochemist Ernst Boris Chain — decided to try again. They read Fleming's old paper. They grew Penicillium mold. And they developed a method to extract and purify penicillin using freeze-drying and chromatography.

Their first test was on a policeman named Albert Alexander, who was dying from a face infection that had spread to his blood. After receiving penicillin injections, Alexander improved dramatically within 24 hours. His fever dropped. His infection retreated. For the first time in history, a bacterial infection was being beaten by a drug.

But Florey and Chain didn't have enough penicillin. After five days of treatment, they ran out. Alexander relapsed and died.

Growing Mold in Bedpans

The problem was scale. Penicillium mold grows slowly and produces penicillin in minuscule quantities. To treat one patient for one week required 2,000 litres of mold culture — the output of hundreds of growing vessels.

Florey's lab couldn't afford proper fermentation equipment. So his team used what they had: bedpans, milk churns, biscuit tins, and bathtubs. They turned the Dunn School of Pathology into a mold farm, growing Penicillium in every available container.

By 1941, they had produced enough penicillin to conduct clinical trials. The results were extraordinary. Infections that had been a death sentence — septicaemia, gangrene, pneumonia — could now be cured in days. But producing enough for the entire Allied military required an industrial solution.

Florey flew to the United States, where the US Department of Agriculture's laboratory in Peoria, Illinois made two critical breakthroughs. First, they found that growing Penicillium in corn steep liquor (a waste product from corn processing) increased penicillin yield tenfold. Second, they discovered a new strain of Penicillium — found on a mouldy cantaloupe melon from a Peoria market — that produced 200 times more penicillin than Fleming's original strain.

By D-Day, June 6, 1944, American pharmaceutical companies were producing 2.3 million doses per month. Enough for every wounded soldier in the Allied forces. The mortality rate from infected wounds dropped from 18% in World War I to less than 1% in World War II.

How Penicillin Works

Penicillin kills bacteria by attacking their cell wall. Bacteria are surrounded by a rigid wall made of a molecule called peptidoglycan — a mesh of sugar chains cross-linked by short peptide bridges. This wall keeps the bacterium from exploding under its own internal pressure (which is about 5 atmospheres — five times the air pressure around you right now).

Penicillin mimics the shape of the D-alanyl-D-alanine end of the peptide bridge. It binds to the enzyme — transpeptidase — that creates the cross-links, blocking it. Without new cross-links, the cell wall weakens as the bacterium grows. Eventually, the internal pressure ruptures the weakened wall, and the bacterium bursts like an overinflated balloon.

This is why penicillin only kills bacteria that are actively growing and dividing — dormant bacteria aren't making new cell wall, so penicillin has nothing to block.

The Resistance Crisis

Fleming himself predicted the problem. In his 1945 Nobel Prize acceptance speech, he warned: "It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them."

He was right. By the 1950s, resistant strains of Staphylococcus were appearing in hospitals. By the 2000s, MRSA (methicillin-resistant Staphylococcus aureus) had become a global health crisis.

The mechanism is evolution by natural selection, running on fast-forward. A single bacterium can reproduce every 20 minutes. In a population of a billion bacteria, random mutations will produce a few individuals with slight resistance to penicillin. If you treat that population with penicillin but don't kill every bacterium — because you stopped the course too early, or took too low a dose — the resistant ones survive and multiply. Within days, you have a population that is entirely resistant.

This is happening today with multiple antibiotics. The World Health Organization has identified antibiotic resistance as one of the top ten threats to global health. We are running out of drugs faster than we can develop new ones.

The story of penicillin is the story of biology at its most powerful — a mold that saves millions of lives, and the bacteria that are learning to fight back.

The end.