Few discoveries in medicine have a more interesting history than the introduction of the sulfonamides into clinical medicine.¹ I feel somehow part of this process only because, having suffered from some febrile illness as a little boy, I distinctly remember being given a medicine that went by the name of “rubiazol” and turned the urine red. The drug was a proprietary form of the first sulfonamide, Prontosil, which revolutionized the treatment of bacterial infections.^1-3

The impetus for this remarkable discovery came from the work of the German chemist Paul Ehrlich, who in the 1880s suggested that certain chemicals could selectively target pathogens without harming the host. Then, in 1909, a group of German chemists working for the I.G. Farbenindustrie synthesized sulfonamide derivatives during their attempt to develop azo dyes for the textile industry. In 1919 Heidelberger and Jacobs noted that several of these azo dyes possessed an in- vitro bactericidal activity. They did not, however, continue their study.¹

In 1932, two other chemists, also from the I.G. Farbenindustrie, resumed studies in that direction and obtained a patent for Prontosil, an orange-red dye sulfonamide derivative found to have antibacterial properties. Soon clinical reports started to appear describing the effectiveness of Prontosil against streptococcal infections. It was not until 1935, however, that interest in Prontosil became widespread as Gerhard Domagk published his classical paper on its effectiveness in experimental streptococcal infections in mice. Soon, investigators in France, England, and the United States entered this new field of chemotherapy. A later review on the introduction of penicillin indicates that by the early 1940s, JAMA, The Lancet, Science, and other journals had published thousands of papers about the sulfonamides.² By 1943, few drugs were as widely prescribed in clinical medicine as the sulfonamides or in as large of doses.³

Sulfonamides were used extensively on soldiers during World War II and significantly reduced mortality rates from wound infections. They were successfully prescribed to treat streptococcal and staphylococcal sepsis as well as bacillary dysentery, and they saved the lives of thousands of children. In 1943 and again in 1944, they were given to Winston Churchill as treatment for pneumonia. As time went on many other sulfa drugs were brought on the market, some used alone, some in combination with other antimicrobials.

For the discovery of the sulfonamides, Domagk was selected to receive the 1939 Nobel Prize in Physiology or Medicine, but the Nazi government did not allow German citizens to accept it. He had his passport taken away, was arrested, and held until he refused the award. In 1947, after the fall of Nazi Germany, he was officially given the Nobel Prize and delivered the Nobel lecture. He died from a heart attack in 1964.¹

Sulfonamides work by interfering with the bacterial synthesis of folic acid, an essential compound for DNA and RNA production. They achieve this by inhibiting the enzyme dihydropteroate synthase, which is critical for folic acid synthesis in bacteria. Since humans obtain folic acid through diet and do not synthesize it internally, sulfonamides specifically target bacterial cells, sparing human tissues. Yet despite their initial success, sulfonamides were not without limitations. Side effects such as allergic reactions, nausea, and kidney damage were relatively common. Their widespread use also led to the emergence of drug-resistant bacterial strains. These challenges underscored the need for new antibiotics with improved safety and efficacy profiles.

The development of sulfonamides inspired a wave of research into other antimicrobial agents. In the decades following their discovery, several natural antibiotics, such as penicillin or streptomycin, and synthetic ones, such as quinolones, were developed. At present sulfonamides are no longer the first-line treatment for most infections, but they are still used for specific conditions, urinary tract infections, certain types of meningitis, and toxoplasmosis. In modern clinical medicine, they are most often combined in a single tablet of sulfamethoxazole and trimethoprim, such as Bactrim or Septra.

From a historical point of view, the discovery of sulfonamides marks the beginning of the antibiotic era. It greatly expanded the arsenal of humanity against disease and represented departure from a time of helpless doctors unable to save their patients from bacterial infections.

Further reading

1. Cohen LS. and Cluff L.E. The Sulfonamides. American Journal of Nursing 1961;61(6):53.
2. Connolly C. Penicillin’s 70th Birthday. American Journal of Nursing 2014;114(12):65.
3. Rosenthal SM. Pharmacology of the Sulfonamide Drug. Scientific Monthly Mar. 1943;56(3):232.