Today we take antibiotics for granted. We put them in our soap, apply them to cuts and scrapes, and take them to treat acne. But in the years before 1935 bacterial infections were a deadly and ever-present risk. People routinely died from minor scratches and cuts that became infected, and infections were so feared that their tell-tale red streaks in an arm or leg immediately prompted amputation. This all changed with the discovery of Prontosil, the first of a class of antibiotic drugs known as sulfa drugs. Penicillin often gets credit as the first antibiotic, but Prontosil and other sulfa drugs had been used to effectively treat bacterial infections for close to a decade before penicillin became available. When it was introduced Prontosil was literally a miracle drug – after taking it patients who were near-death were revived and healthy within hours.
Prontosil, a brilliant orange-red compound, started it’s life not as an antibiotic, but as an industrial dye. It was produced by the German chemical manufacturing company I.G. Farbenindustrie and was used to dye wool and leather. At the time some scientists were looking for a chemical that could treat infections by damaging bacteria while leaving human cells unharmed – a so-called ‘magic bullet’. Two of these scientists were Gerhard Domagk and Josef Klarer both of whom worked at Bayer (of aspirin fame), the pharmaceutical division of I.G. Farbenindustrie. They were particularly interested in using chemical dyes as antibiotics. The thinking seemed to be: when a dye colors a bacterial culture it sticks to the bacteria, so maybe it would also seek out, stick to, and somehow kill bacteria in a human. This is pretty sketchy logic, but there wasn’t much else to go on at the time.
The two worked as a team. Klarer made chemical dyes in the laboratory and Domagk tested their clinical effect. By starting with a basic chemical structure and modifying it in small ways, Klarer was able to produce hundreds of dyes for Domagk to screen. Domagk’s notes, now archived at Bayer, indicate that he tested the effect of each dye on several different types of bacteria, and in a testament to the ambition and naivete of the time, also considered their effect on cancer. In 1932 Domagk tested Prontosil. In his experiments he used a strain of streptococcus bacteria, the same type of bacteria that is responsible for scarlet fever, rheumatic fever, pneumonia, and strep throat, among other diseases. He exposed cultures of the bacteria grown in glass dishes to the dyes to determine whether any of the dyes were capable of killing the bacteria outright. But after exposure to Prontosil the bacteria continued to thrive. Even so, Domagk knew that a chemical might have a different effect on a bacterial infection in a living body, so he tested some of the dyes, including Prontosil, in mice. He infected a group of mice with a lethal dose of streptococcus and then gave some of the mice Prontosil while others received no treatment. Sadly, but not unexpectedly, all of the mice that did not receive any treatment were dead within two weeks, but the mice that were given Prontosil never got sick. It was a promising result. But of course, preventing infection in a mouse doesn’t necessarily mean curing the same infection in a human.
Domagk partnered with a nearby hospital to test Prontosil in humans. But the ultimate test of his new drug would hit much closer to home. Around Christmas time of 1935 Domagk’s six-year-old daughter Hildegard tripped and fell while holding an embroidery needle. The needle was driven into the palm of her hand and she was taken to the hospital where it was removed. But a few days later she began to run a fever and her hand became swollen. Red stripes crept up her arm as the infection spread, and her condition steadily deteriorated as her fever rose. Her doctor recommended amputating her arm, but it seemed that the infection had already poisoned her blood leaving her with little chance of survival even after an amputation. Tests showed that Hildegard was infected with streptococcus, the same bacteria that had failed to kill mice that were given Prontosil. Faced with his daughter’s imminent death, Domagk made the desperate decision to give her Prontisil, which had been minimally tested in humans at the time. He gave her several massive oral doses of over ten grams each. Amazingly there were almost no side effects. Hildegard walked out of the hospital two days later, completely cured.
By the end of 1935 Domagk had published his laboratory results showing that Prontosil prevented infection in mice alongside the positive results of the clinical trials, although he omitted the case of his daughter. The report was met with skepticism. At the time a lot of doctors didn’t even believe that it was possible to fight diseases with chemical drugs. But the results of the clinical trials were quickly reproduced in a British hospital where Prontosil was shown to cure puerperal fever, a bacterial infection associated with childbirth (and one of those Oregon-Trail-type diseases most people today have never heard of). In fact, during the course of the study the head physician developed an infection in a cut on his finger. Initially skeptical of Prontosil, he was given the new drug as a last resort and made a full recovery. Later that year Prontosil gained widespread recognition when it was used to treat a severe strep throat infection in President Franklin D. Roosevelt’s son.
But what about Prontosil not killing bacteria grown outside of a living body? Within a year of Domagk’s publication, scientists at the Pasteur Institute figured out the answer to this question. When Prontosil enters the body it is broken down into smaller pieces. One of these pieces, called sulfanilamide, is the active drug, meaning it is responsible for killing bacteria. Chemical manufacturing companies already produced tons of sulfanilamide every year as an intermediate in the dye-making process, so there was a large supply of the drug readily available.
You would think this would be good news. But there’s a potentially darker side to this story. Sulfanilamide was discovered in 1908, meaning it’s patent had expired by 1935. If the drug were released without a patent anyone could manufacture and sell it – and in fact that is what happened. Domagk completed his experiments showing that Prontosil prevented infection in mice in 1932, but he didn’t publish these results until late 1935. The scientists at the Pasteur Institute accused Bayer and Domagk of having discovered that sulfanilamide was the active component of Prontosil during this intervening period, and delaying publishing their results while they searched for a similar drug that they could patent. The Pasteur Institute scientists argued that if Domagk had immediately made his results public, countless lives could have been saved in the years between 1932 and 1935. However, Domagk’s notes indicate that he never tested sulfanilamide and was unaware that it was the active component of Prontosil. He likely delayed publication of his results while he confirmed that the drug would be safe for humans. Even so, the charges against Domagk highlight the kind of ethically complicated situations that can arise when life-saving science is mixed with a desire to maximize profits. Making money and saving lives can’t always go hand in hand, and this conflict continues today and contributes to the unpopularity of pharmaceutical companies.