Sulfonamide: the First Antibacterial Agent Acting Selectively
المؤلف:
Ola Sköld, M.D., Ph.D
المصدر:
Antibiotics and Antibiotic Resistance
الجزء والصفحة:
p5-8
2025-07-08
491
Louis Pasteur, a great French microbiologist of the nineteenth century, formulated and proposed what was called the germ theory of disease, the concept that infectious disease was caused by microorganisms. Later, Robert Koch at the Imperial Health Office in Berlin provided proof, with Bacillus antracis as an example, that there is a definite causal relation of a particular microorganism to a particular disease. From these ideas Koch formulated his postulates for characterizing a pathogenic microbe:
1. The organism is found regularly in the lesions of the disease.
2. It can be isolated in pure culture on artificial media.
3. Inoculation of this culture produces the disease in experimental animals.
4. The organism can be recovered from lesions in these animals.
Based on these basic ideas, Paul Ehrlich at the Royal Institute for Experimental Therapy in Frankfurt am Main advanced the idea of direct selective action of a drug on infecting microbes. His expression for this was the ‘‘magic bullet,’’ which would exhibit a greater affinity for pathogenic bacteria than for host cells. For this selective action he coined the word chemotherapy. Ehrlich further observed that dyes-stained different cell components selectively and proposed the idea that organic stains taken up, particularly by living cells, could have a therapeutic effect by interfering with bacterial infections.
In the 1930s, these ideas led Gerhard Domagk, who was working at the Institute of Experimental Pathology at the I.G. Farbenindustrie in Elberfeld, Germany, to the discovery of Pron tosil rubrum (4-sulfonamide-2,4-diaminoazobenzol, Domagk 1935) (Fig. 1); a chemically synthesized dye of red color, which showed an effect against bacterial infections in animals. It was, however, inactive in vitro. Jaques and Therese Tréfoüel of the Pasteur Institute in France could show that patients treated with Prontosil excreted a simpler product, sulfanilamide, which was active in vivo as well as in vitro against the growth of bacteria. This was a dramatic development since it finally established Ehrlich’s principle of chemotherapeutic action. Sulfanilamide isa colorless substance and not a dye, partly contradicting the theory leading to its discovery.
Fig1. Sulfonamide. Ampoule containing 5mL of Prontosil rubrum for injection, the first sulfonamide preparation for clinical use.
Sulfanilamide was set free from the dye by hydrolysis in vivo in animal experiments. Sulfanilamide was thus the first antibacterial agent to act selectively. The first trials of Prontosil rubrum on animals were performed by Domagk in 1932. He could show that mice infected experimentally with Streptococcus pyogenes by injection into the peritoneum were protected from peritonitis with this agent. The results were published in Deutsche medizinische Wochenschrift in 1935, and sulfonamides were soon used widely for the clinical treatment of infections with streptococci, staphylococci, meningococci, and other severely pathogenic bacterial agents. Domagk’s work is unjustly forgotten today but was much appreciated by his contemporaries, and at the end of the 1930s he was nominated for the Nobel Prize in Physiology or Medicine. The Nazi regime of that time in Germany had, however, declared that it did not want to see any German as a Nobel laureate, probably because of the Nobel committee’s choice of earlier Nobel Peace Prize laureates. The German government of that time tried through its embassy in Stockholm ,and also directly through the foreign office in Berlin, to interfere with the work of the Nobel committee at the Karolinska Institute in Stockholm. The Nobel committee, with its chairman pathology professor Folke Henschen, stood up to the pressure, however, and asked the medical faculty at the Karolinska Institute to award the prize to Domagk. In his memoirs from 1957, Folke Henschen, who personally knew Gerhard Domagk, mentioned that in the night following that day in October 1939 when the prize was announced, Domagk was arrested by Nazi soldiers in his home in Wuppertal and taken to jail. Next morning, when the prison director made his daily round, he met with Domagk, who did not seem to fit the environment. ‘‘Who are you?’’ he asked. ‘‘I am Professor Gerhard Domagk of the University of M¨ unster.’’ ‘‘Weshalb sind Sie hier denn?’’ Domagk’s reply: ‘‘Ich habe den Nobel preis bekommen.’’ The Nazi authorities did not allow Domagk to travel to Stockholm to receive the prize in December 1939. He did not go to Stockholm to receive the medal and the diploma until 1947, but because Alfred Nobel’s will specifies that the offer of prize money expires on the day of the award ceremony, he received no prize money.
Sulfonamides chemically synthesized beginning with Domagk’s Prontosil rubrum were widely used as efficient and inexpensive antibacterial drugs for the treatment of both gram-positive and gram-negative pathogens, and they had a deep impact on the fate of Europe. In December 1943, British Prime Minister Winston Churchill had just completed a complex series of meetings, among them the fateful conference with Franklin D. Roosevelt and the Soviet leader Joseph V. Stalin in Teheran. He was on his way to meet with the U.S. General Dwight D. Eisenhower in Tunis to discuss the D-day landings when he contracted a severe case of pneumonia. His doctor, Lord Moran, decided to treat his important patient with a new drug, a sulfonamide. The treatment was successful, and there is little doubt that the novel sulfa drug defeated the pneumonia and probably saved the life of this important European leader.
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