special feature

Never say dye

A brief, colorful history of sulfa drugs, leading to Gerhard Domagk’s discovery of prontosil, the first commercially available antibiotic.

J.C.A. Morrant, MBBS, DObst, the Ukraine, where he met many of RCOG, DPM, FRCPC the captains of death: cholera, which Domagk (pictured above) and his colleagues killed thousands; typhoid fever, which synthesized thousands of compounds over erhard Domagk (1895–1964) caused a true decimation of Napoleon’s 5 years before they were successful. was awarded the Nobel Prize army in 1812; gas gangrene, in which Gin 1939 for his research into the exotoxin of Clostridium perfrin- vesuvin. He proved that the brilliant the antibacterial actions of a ruby-red gens rotted flesh and produced a nitro- blue rods he discovered, “Koch’s dye, prontosil (sulfonamidocrysoidine). genous gas with a sickening smell that Bacillus” or Mycobacterium tubercu- Germans were forbidden to accept the made tyros faint; and tuberculosis, the losis, caused tuberculosis. Freidrich prize and the Nazis imprisoned Dom - greatest killer of all time. Even a small Loeffler called the lecture “pure agk until he refused it, a brutal act that wound could cause death from sep- unadulterated gold.” Ehrlich agreed: left him with lifelong spells of palpi- ticemia. “[it was] the most important experi- tations and depression. He accepted Bacterial infections were believed ence of my professional life.” He had his prize in 1947, after the Third Reich incurable; “obviously” a drug that could been fascinated by dye since his stu- had collapsed, “born of lies and suffo- kill bacteria would also kill healthy dent days; friends joked about his col- cated under its cruelty and blood,” he blood and body cells. Voltaire’s joke, ored fingers. Ehrlich believed a dye wrote. “the art of medicine consists of amus- could be made that would act like a Domagk wore his old tails and a ing the patient until nature cures the “magic bullet,” fix to a bacterium, kill borrowed waistcoat to the ceremony. disease,” seemed cruelly apt. Domagk’s it, and leave other cells unharmed. He was exhausted, celery-thin, and ac- war experiences haunted him. He kept Ehrlich experimented with thou- quainted with grief; his mother had a skull on his desk as a memento mori sands of dyes. He also studied Bé- died from starvation during the war and wrote, “I swore before God and champ’s work, but mistakenly thought and the Nazis sent his son Wolfgang, myself to counter this destructive that Trypanosoma brucei, the proto- aged 15, and his classmates to attack mad ness.” zoan causing African sleeping sick- 6 million Soviet troops. As humble as Others had sought a cure for infec- ness, was related to Treponema pal- the Curies, Domagk described his wife, tions. Antoine Béchamp synthesized lidum, the spirochete causing syphilis. Gertrude, and himself as “meagre.” arsanilic acid in 1859 and found it fee- Ehrlich believed that an arsenic com- Three decades earlier Domagk had bly effective against African sleeping pound might kill the spirochete. He volunteered to serve as a soldier in the sickness and yaws, but too toxic for tested hundreds of arsenicals before First World War. After being wound- use. In 1882 Paul Ehrlich and an audi- giving the work to Dr Sahachiro Hata, ed, he served as a medical orderly in ence of eminent physicians listened in who synthesized arsphenamine (which stunned silence as Robert Koch, a they called Salvarsan 606 because it This article has been peer reviewed. country doctor, explained how he had was the 606th drug they tried) in 1910. Dr Morrant is a psychotherapist in Rich- stained pus from a tuberculous ab - Arsphenamine, the first chemothera- mond, with an interest in literature, history, scess with methylene blue (developed peutic drug (a word coined by Ehrlich), and gardening. by Ehrlich) then counterstained it with cured syphilis. Many patients could

68 BC MEDICAL JOURNAL VOL. 54 NO. 2, MARCH 2012 www.bcmj.org special feature not tolerate the side effects of arsphen- a mine and Ehrlich counted himself a failure despite being awarded the Nobel Prize in 1908 for his work on immunology. Streptococcal infections can also be captains of death. In 1924 Presi- dent Calvin Coolidge’s son blistered his heel playing tennis and died a week later from streptococcal septicemia. Streptococci caused four of the most lethal hospital diseases: cellulitis, ery- sipelas, wound infections, and puer- peral fever, all mainly spread by the hospital staff. From the days of the powdered wig and gold-topped cane Box of five ampoules of pronotsil, circa 1936–1940. This free sample, produced by Bayer Germany, women were safer from puerperal was probably intended for the Middle Eastern market. (Photo by Science & Society Picture Library/SSPL/Getty Images). fever if delivered at home, as doctors were often a grubby lot. reproduce and are destroyed by the own concoctions. Massengill, a rich During the 1920s and 1930s immune system. manufacturer, produced Massengill’s Domagk shared Workroom Four at the In 1935 the Domagks’ 6-year-old Sulfanilamide Elixir. The sulfanil- Bayer factory with two chemists, daughter Hildegard pricked her hand amide was dissolved in diethylene Josef Klarer and Fritz Mietzsch. They with a needle. As she lay dying from glycol, an industrial solvent. One hun- synthesized thousands of compounds septicemia her surgeon planned to dred fifty patients developed uremic for him to test against a battery of bac- amputate her arm. Domagk, aghast, encephalopathy and died from renal teria, including a virulent strain of stuffed the little one with prontosil. failure. The chemist, Harold Watkins, streptococcus. Five years passed with- She recovered. shot himself in the heart. The tragedy out success. Then in 1932 Klarer in- In England, Leonard Colebrook, a gave teeth to the FDA and many patent serted a sulfur atom into a dye mole- preternaturally cautious researcher, drugs disappeared. cule. The results were surprising, even reduced the death toll from puerperal The sulfonamides saved hundreds shocking. First it worked, killing strep- fever dramatically with sulfanilamide of lives after the attack on Pearl Har- tococci responsible for wound infec- in 1936. That same year, President bor. In 1943, Winston Churchill devel- tions, pneumonia, puerperal fever, F.D. Roosevelt’s son developed a strep- oped pneumonia with atrial fibrilla- meningitis, gonorrhea, and so on. Sec- tococcal sore throat and sinus infec- tion and congestive cardiac failure. ond, French workers soon showed that tion. He was near death when Eleanor He was given “M and B, 693,” i.e., the dye was unnecessary; it was the Roosevelt agreed for prontosil to be sulfapyridine manufactured by May sulfa part of the molecule that cured. given him and he slowly recovered. and Baker at their 693rd try. After this The finding refuted Ehrlich’s belief Prontosil became instantly famous. It the sulfonamides were slowly eclip - that a bactericidal drug would be a was successful against an outbreak of sed by penicillin and a phalynx of dye. Third, the curative agent was meningitis in the US Army. Eleanor antibiotics with fewer side effects and sulfanilamide, a common industrial Roosevelt said, in her breezy way, broader antibacterial spectra. Howev- chemical, made by the ton, first syn- “The Marines I have seen around the er, a few sulfonamides live on: for thesized by Paul Gelmo in 1909, so world have the cleanest bodies, the example, in the mixture trimethoprim- the patent had long expired. The sul- filthiest minds, the highest morale and sulfamethox azole. Domagk once said, fonamides are bacteriostatic drugs. the lowest morals of any group of ani- “it is easy to kill but very difficult to Prontosil is a prodrug, metabolized to mals I have ever seen.” The sulfon- save lives.” He helped save the lives sulfanilamide. Body cells take in folic amides prevented a huge number of of millions. acid but the streptococci must synthe- working hours being lost to invalidism And whatever happened to size it. Sulfona mides compete with due to gonorrhea in the armed forces. Domagk’s young son Wolfgang? He streptococci for the enzyme dihy- Some officers gave them to their men couldn’t beat the Russians, but trudg - dropteroate synthase, which converts before and after a date. There was an ed home and spent Christmas with his para-aminobenzoic acid to folic acid. “orgy of overprescribing” and patent family. Without folic acid streptococci cannot drug firms began to manufacture their

www.bcmj.org VOL. 54 NO. 2, MARCH 2012 BC MEDICAL JOURNAL 69