The history of sulphonamides
The first sulphonamide compound, a red crystalline powder, was synthesised and characterised in 1908 by Paul Gelmo, a chemistry student at the University of Vienna. It was not until December 1931, however, that such compounds, also known as sulpha drugs, were found to have antibacterial effects. This was demonstrated by Gerhard Domagk, a German pathologist and bacteriologist, who began testing different sulphonamide molecules on mice infected with hemolytic streptococci derived from a human subject.
After testing 3000 compounds Domagk discovered one particularly promising compound - KL 695, or prontosil rubrum - which had been synthesised by Josef Klarer and Fritz Mietzsch as part of a research program at IG Farben designed to find dyes that might act as antibacterial drugs in the body. By October 1932 Domagk had found that KL 695 was capable of destroying streptococci in both mice and rabbits, even in low doses. In one experiment fourteen mice who received the compound all survived whereas the other group that did not get it all died (Leach).
Domagk was so encouraged by the results he got in his experiments with prontosil that he decided to risk administering the same compound to his six-year old daughter, Hildegard. This he did on 4 December 1935 in a desperate attempt to prevent her hand being amputated. It had become severely infected with streptococci after a needle got wedged in her hand on falling down some stairs. Fortunately Domagk's gamble paid off; Hildegard was completely cured within a week. She was just left with a permanent red stain on her arm where the drug had been injected. Meanwhile similarly positive findings were made in human clinical trials over the next three years. These were conducted at Wuppertal-Elberfeld and Dusseldorf University Hospital. The compound was patented as a drug in 1934 and went on sale in 1935 as Prontosil (Leach).
Figure 3.2.1: Small sample of Neo Prontosil (azosulfamide), one of the sulphonamide compounds synthesised in the 1930s (Credit: Science History Institute).
In November 1935 a team of French scientists at the Pasteur Institute, led by Daniel Bovet, discovered that the anti-streptococcal action of Prontosil was down to its sulfanilamide ingredient. One of the advantages of this finding was that sulfanilamide was much easier and cheaper to produce than Prontosil. Unlike Prontosil, it also did not turn patients' skin red. Other sulphonamides soon after started to appear on the market. Approximately 5,000 sulphonamide derivatives had been synthesised by the mid-1940s (Leach).
Figure 3.2.2: Gerhard Domagk, 1949 (Credit: Bayer Corporation). Domagk (1895– 1964) completed his medical degree in 1921. Domagk developed a strong interest in finding an antibacterial drug after he witnessed many wounded soldiers succumbing to gas gangrene bacterial infections when working as a medical assistant in field hospitals during World War I. In 1927 Domagk joined IG Farben, a German pharmaceutical company, where he set up a pharmacology laboratory to test out the antibacterial activities of different synthetic dyes. While Domagk was awarded the Nobel Prize in Physiology or Medicine in October 1939 for his discovery of Prontosil, he was forbidden by the Nazi regime to accept the prize and when he attempted to do so he was arrested and thrown into jail for a week. Domagk was only released after signing a letter turning down the Prize. Domagk finally collected his prize in 1947.
Figure 3.2.3: Prontosil ampoules. These samples of Prontosil were intended to be injected into soldiers in the Middle East during World War II (Credit: Wellcome Images).
The mass production of sulphonamides in part reflected their success in treating a wide range of bacterial infections. Where the drug had its first most dramatic impacts was in reducing the number of deaths from puerperal sepsis caused by streptococcal infections which up to the 1940s was one of the leading causes of maternal mortality. The first person to demonstrate the value of the drug in this area was Leonard Colebrook, a physician at Queen Charlotte's Hospital in London. He was helped in this endeavour by his youngest sister, Dora. She managed to trace the source of the puerperal fever infections within the hospital by investigating samples of streptococcal bacteria from patients, their relatives and hospital staff. After establishing Prontosil to be effective for the treatment of streptococcal peritonitis in mice, Leonard Colebrook and his colleagues began using the drug in early 1936 to treat women with puerperal fever caused by haemolytic streptococci. By the end of 1936 they had treated 64 patients with the drug, all of whom experienced a remarkable improvement (Colebrook, Kenny).
Figure 3.2.4: Leonard Colebrook, n.d. (Credit: Walter Stoneman, Wellcome Images). Colebrook (1883-1967) was born in Guildford, Surrey. He undertook premedical studies at the London Hospital Medical College in London. Following this, he received a scholarship to study at St. Mary's Hospital Medical School in London, where he completed his training in 1906. Between 1907 and 1912, Colebrook worked in the Inoculation Department at St Marys, where he investigated vaccines together with Almroth Wright to treat infectious diseases. Colebrook began investigating puerperal sepsis after working as a military doctor in World War I. In 1928 he secured funding from the Medical Research Council, a government research agency of UK, which allowed him to look for the specific bacteria that caused puerperal fever and to develop a cure. He carried out the work at Queen Charlotte's Hospital.
Figure 3.2.5: Chart documenting a typical fall in the fever of a patient infected with puerperal sepsis and decline of bacteria in blood cultures following treatment with Prontosil (Colebrook, Kenny).
Figure 3.2.6: Table from Colebrook, Kenny. This table indicates that the death rate for patients treated with Prontosil was much lower than with other treatments. In other cases the mortality rate was over 20 per cent. By comparison it was just over 4% in patients treated with Prontosil.
Figure 3.2.7: Front cover of article published by Dora Colebrook (1884-1965), summarising her work on puerperal fever. The article appeared in an MRC collection of articles (Credit: Sriskandan).
Dora (1884-1965) was born in Guildford, Surrey. She completed her medical degree at the Royal Free Hospital in London in 1915 and her M.D. from University of London in 1919. Following this she gained a diploma in bacteriology. After her training, Dora Colebrook worked as a gynaecologist at Jesse's Hospital in Sheffield. She then moved to Cambridge where she took over the medical practice of Dr Milne, another female doctor in Cambridge, and her role as both an Honorary Medical Officer for the Cambridge Home of Mercy, a female refuge that helped destitute women get work, and as an honorary physician of the Shelter for Girls at 14 Downing St Cambridge. In 1930 Dora Colebrook became a Leverhulme Research Fellow at Queen Charlotte's Hospital, London, where she began working with her brother on the epidemiology of puerperal sepsis. Using immunological methods to identify individual streptococcal strains, Dora Colebrook discovered that the streptococcal strains causing puerperal sepsis were not unique to the women suffering from the condition and could be found in the respiratory tracts of people treating and caring for them. She demonstrated that the bacteria that caused puerperal fever travelled far more often with the doctor as opposed to the patient. Based on this she concluded that the bacteria travelled from the birth attendant to the patient
The popularity of Prontosil was also boosted by the news, in December 1936, that the drug had cured a severe throat infection suffered by Franklin Roosevelt Jr, the 22 year old son of the President of the United States. So high were the expectations for sulphonamides that in 1939 one researcher declared, 'Seldom has any new drug aroused so much or so rapidly gained attention ...The advent of sulfanilamide has established beyond all doubt that effective chemotherapy of microbial diseases is attainable' (Hench, Bauer, Dawson).
Sulphonamides were quickly seized upon by the military as a way of preventing mortality from bacterial infections on the battlefield. They were used by both sides in the Spanish Civil War (1936-39) for various purposes. By the start of the Second World War sulphonamides had become a regular part of army supplies. Each soldier carried a pouch of white sulpha powder to sprinkle on any open wounds to ward off infections and vials of sulpha tablets to treat and prevent dysentery (Arnold).
Just how widespread sulphonamides became can be judged by the fact that American production of sulpha drugs rose from 350,000 to 10 million pounds between 1937 and 1942 (Arnold). Meanwhile Britain was also stepping up production. Here the annual quantity of sulphanilamide produced rose from 53 tons to 500 tons between 1942 and 1945 and that of other sulphonamides from 10 to 100 tons. By 1942 the country was also producing 80 tons of sulphathiazole and sulphaguanidine per year. Nevertheless even this proved insufficient to meet the demands of treating war wounds, gonorrhoea and dysentery so the drugs were reserved for the troops. Prescriptions for civilians only became possible after March 1944 once there was adequate production of sulphathiazol (Davenport).
Figure 3.2.8: Different sulphonamide samples.
Figure 3.2.9: Photo of Winston Churchill convalescing in Marrakesh, Morocco, c.31 December 1943. Credit: Ministry of Information, Second World War, Imperial War Museum. He was successfully treated for bacterial pneumonia with sulphapyridine (M&B 636), a sulphonamide produced by the British company May and Baker. Churchill was so taken with the treatment that he put out a bulletin stating: 'This admirable M&B, from which I did not suffer any inconvenience, was used at the earliest moment; and after a week's fever, the intruders were repulsed…. The M&B … did the work most effectively. There is no doubt that pneumonia is a very different illness from what it was before this marvellous drug was discovered.' The same drug was also used to save Nero, the Royal Circus lion, from pneumonia (Glasgow Evening News, Jan 1944).
Sulphonamides proved particularly helpful in decreasing the number of deaths from penetrating wounds, especially those on the head. They also played a significant role in the war waged in the Pacific, where American troops proved better equipped to deal with dysentery than their Japanese opponents because of their greater access to sulphonamides (Arnold).
Another area where sulphonamides proved beneficial was in the treatment of gonorrhoea, a venereal disease which although not fatal took a heavy toll on manpower due to disability. The first reports that sulphonamides could be effective against gonorrhoea appeared in 1937. One study, carried out by Johns Hopkins Clinic, indicated the gonorrhoeal symptoms of patients who received sulfanilamide usually disappeared by the fourth day. A total of fifty-eight patients were treated, six of whom failed to respond. They all received four daily doses of sulfanilamide for four weeks. Over this time the dosage was slowly decreased from 4.8 to 1.2gm (Colston, Dees, Harrill). Similarly positive results were reported for a study carried out at a venereal clinic at St Mary's Hospital in London in 1937 which analysed the use of sulphanilamide treatment in 633 gonorrhoea cases. Those who received the treatment responded much faster and had fewer relapses than those given standard therapy (Cokkinis, McElligott). One trial conducted by the British army in 1937 also demonstrated that sulphonamide treatment could significantly cut down the length of time patients with gonorrhoea needed to stay in hospital and were absent from active service (Harrison).
Figure 3.2.10: Standard individual prophylactic pack given out to US soldiers during World War II who feared they had venereal disease (Credit: WW2 US Medical Research Center, 'Venereal disease and treatment during WW2'). The pack contained, among other things, a tube of ointment (green) that contained sulfathiazole, a sulphonamide derivative.
The dramatic impact of sulpha drugs on gonorrhoea was captured by the data collected by the US Army. This showed that such therapy had managed to cut down the number of days gonorrhoea sufferers spent in hospital from 50 to just 22 in the years between 1934 and 1941. It also reduced the number of patients who experienced complications from the disease from 28 to 6 per cent (Benedek).
Nonetheless, the large-scale indiscriminate use of sulphonamides came at a cost. Bacterial resistance was noted as early as 1937 in gonorrhoea cases treated with sulpha drugs at Johns Hopkins Hospital in Baltimore, USA. The doctors reporting the resistance were so concerned with this finding and the fact that the drug could cause side effects that they were prompted to issue a word of warning against the indiscriminate use of the drug and that it should not be made available to the general public. They argued that it 'should be obtainable only on a physician's prescription under whose care the particular case can be thoroughly and adequately followed' (Colston, Dees, Harrill).
Bacterial resistance to sulpha drugs had become so widespread that by the end of the war they had largely been abandoned for the treatment of penetrating wounds and replaced with penicillin. Sulphonamides, however, continued to be used to treat burns, venereal disease and urinary tract infections (Arnold).
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