Sulphonamides: A Story of Life and Death

The discovery of the first antibiotic is widely credited to Sir Alexander Fleming and providential scientific serendipity. As the legend goes, a care-free Fleming returned from a long holiday to find that his Staphylococcus agar plates had been cross-contaminated with mould. Luckily, he didn’t just toss the ruined plates in the chemicals bin but noticed that the ‘Staphylococcus colonies became transparent and were obviously undergoing lysis (cell disintegration) […] the broth in which the mould had been grown at room temperature […] had acquired marked inhibitory, bactericidal and bacteriolytic properties to any of the more common pathogenic bacteria’ (Fleming, 1929). And this makes for a lovely story – a story of charming accidents, good prevailing over evil and a heroic knight stumbling upon the anti-prokaryotic Holy Grail. But alas, the origin of the first antibiotic is a shade darker and actually begins in 1932 in the German chemical and pharmaceutical conglomerate IG Farben.

The IG Farben scientists had been investigating the ability of coal-tar dyes to fight bacterial and parasitic pathogens for a couple of years when a team, led by Gerhard Domagk, discovered a red dye which could protect mice from bacterial infection. The dye was named Prontosil, and it was immediately patented. It functioned as a prodrug – it could effectively impede streptococci-related infections, such as blood infections, puerperal fever and erysipelas once metabolised in vivo but had no antibacterial activity in vitro. Inside the organism, Prontosil was broken down to the inactive dye component and an active compound, known as sulphanilamide which inhibits bacterial growth and division. Sulphanilamide was already a ubiquitous chemical in the process of dye-making and its patent had long expired. This meant that Prontosil could not be successfully patented by IG Farben and so sulphonamide drugs became freely available to everyone.

One of the first successful treatments with Prontosil took place in London at the Queen Charlotte’s Hospital only three years after their initial discovery. In the early 20^th century, puerperal fever posed a large threat to women who had recently given birth with 45% mortality rates. Ironically, due to poorer hygiene conditions in hospitals, doctors were infecting women with unclean hands, contaminated instruments, as well as dressings and bedding. Puerperal fever is caused by the Streptococcus pyogenes bacterium invading the uterus and surrounding tissues after birth. It manifests quickly, following infections, and is characterised by a high fever and low abdominal pain. Attempts to introduce preventative measures proved futile so the Medical Research Council recruited Leonard Colebrook, an expert on bacterial chemotherapy, to find a cure. Colebrook identified streptococci as the causative bacterial agent and proceeded to test the sulphonamide-based drugs discovered a few years earlier in Germany in disease mouse models. The promising results obtained from mice suffering from puerperal fever motivated him to attempt to treat 106 women with the antibiotic. The drug dosage was varied depending on the severity of the symptoms and treatment proceeded for an average of twenty days. 98 women survived the treatment and were cured. Comparison of puerperal fever mortality rates at Queen Charlotte’s Hospital before and after antibiotics were introduced showed a 66% decrease in deaths.

Leonard Colebrook’s findings inspired trust in the sulphonamide-based drugs and bacterial chemotherapy more broadly. Most famously, Prontosil saved the life of U.S president Franklin D. Roosevelt’s son when a streptococcal throat infection took a life-threatening turn. The treatment was reported in The New York Times, ushering in the era of antibiotics. Soon drugs like Prontosil were widely used in hospitals to treat a range of bacterial infections. The red dye drug saved countless of lives and paved the way for the development of penicillin as a mass-produced medicine in the 1940s.

The lasting impression that sulphonamide-drugs made on modern medicine also extends to the regulation procedures that inspect the safety of food, drugs and cosmetics sold to the public. As Prontosil could not be patented, hundreds of pharmaceutics companies were free to produce and sell the drug. They manufactured different forms of sulphonamide-drugs in different solutions, with different flavours in what is now referred to as the ‘sulfa craze’. In 1937 the S. E. Massengill Company released the raspberry-flavoured ‘Elixir Sulphanilamide’ which contained the highly toxic diethylene glycol. No animal testing or clinical trials took place to ensure the safety of the new drug as this was not yet required by law. At least 100 people died after taking the substance. Widespread outrage instigated a thorough federal investigation into the drug. The owner of S. E. Massengill denied any fault but the chemist Harold Watkins, who was responsible for preparing the sulphanilamide committed suicide while awaiting trial. The outcome was the passing of the 1938 Food, Drug and Cosmetic Act, which mandates all drugs be tested on animals and allowed on the market only after FDA approval. The Act is still in place, protecting consumers from products whose dangers far outweigh their benefits.

Sadly, the great legacy of Prontosil is tainted by the circumstances of its discovery in Nazi Germany. Gerhard Domagk was awarded the Nobel Prize in Medicine in 1939 for synthesising the first drug that effectively treats bacterial infections. However, the Nazi party had forbidden German citizens from accepting the Nobel Prize following the receipt of the Peace Prize by a prominent critic of the regime. Domagk was forced to give up his prize after being arrested by Gestapo, the secret state police, and imprisoned for a week. But the Nazis’ part in this story does not end here. Heinrich Hörlein, the executive director that supervised Domagk and the dye project, was a member of the Nazi Party, along with several other important directors. He was involved in an IG Farben subsidiary company that produced and supplied Zyklon B, the cyanide-based pesticide, responsible for the death of over one million people in gas chambers. The German chemical and pharmaceutical conglomerate relied heavily on the nearby concentration camps for slave labour to power the IG Farben plant and for medical experiments. IG Farben scientists regularly tested new drug preparations on concentration camp prisoners after purposefully infecting them with an incurable disease. After the war was over, 24 of the conglomerate’s directors were prosecuted and most were incarcerated for war crimes.

The story of the first antibiotics is not a comforting heroic tale. It is a story of contradictions and moral reconciliations. Sulphonamide-based drugs have saved thousands of lives directly through their drug action, as well as indirectly through popularising the concept of antibiotics and implementing the 1938 Food, Drug and Cosmetic Act. But Prontosil was synthesised at the expense of the well-being and the lives of concentration camp inmates. Stories like this one convey the Janus-like quality of the history of medicine. As time goes by, only the pretty picture survives in the mainstream consciousness, but it is important to appreciate the sacrifices made in the name of scientific progress.

Mery Shahin is studying for a PhD in the Department of Medicine at Imperial College London 

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