(b. Lagow, Brandenburg, Germany, 30 October 1895; d. Burgberg, Germany, 24 April 1964)
medicine, chemistry, pharmacology.
Domagk, the son of a teacher, decided to study medicine while still at a scientifically oriented grammar school in Liegnitz (now Legnica). During his first term at the University of Kiel, World War I broke out and Domagk volunteered for active service with a German grenadier regiment. After being wounded he transferred to the German army medical corps and received his M.D. at Kiel in 1921. For a short while he worked as an assistant to the chemist Ernest Hoppe-Seyler and in 1924 became reader (Privatdozent) in pathology at the University of Greifswald. In 1925 he accepted a similar post at the University of Münster and married Gertrud Strube. They had four children, and his only daughter was one of the first patients to be treated successfully with prontosil rubrum for a severe streptococcal infection.
Domagk became extraordinary professor of general pathology and pathological anatomy at Münster in 1928 and ordinary professor in 1958.
In 1924 Domagk published a paper on the defensive function of the reticuloendothelial system against infections. As a result of that paper and of his wellknown interest in chemotherapy the directors of the I. G. Farbenindustrie appointed him—at the age of thirty-two—director of research at their laboratory for experimental pathology and bacteriology at Wuppertal-Elberfeld. It was the turning point of his career.
Since Paul Ehrlich’s discovery of arsphenamine in 1909, chemotherapy had advanced in the field of protozoan and tropical diseases, but hardly any progress had been made in regard to bacterial infections of man; and the I. G. Farbenindustrie had decided on further testing of potential antibacterial agents, along the lines laid down by Ehrlich. Domagk’s interest centered on the so-called azo dyes, in which one hydrogen atom had been replaced by a sulfonamide group. These dyes, which had been developed as early as 1909 by H. Hörlein and his collaborators, conferred on textiles a high resistance to washing and light, because of their intimate combination with wool proteins.
In 1932 Domagk’s colleagues, the chemists Fritz Mietzsch and Josef Klarer, synthesized a new azo dye, hoping that it would prove to be a fast dye for treating leather. It was -4′ sulfonamide-2-4-diaminoazobenzol, which they named prontosil rubrum. Domagk early recognized its protective power against streptococcal infections in mice and its low toxicity, but he withheld publication of his findings until 1935. His paper “Ein Beitrag zur Chemotherapie der bakteriellen Infektionen” has become not only a classic but—measured by strict experimental and statistical yardsticks—a masterpiece of careful and critical evaluation of a new therapeutic agent.
As early as 1933 A. Förster had reported the dramatic recovery of an infant with staphylococcal septicemia after treatment with prontosil rubrum, but Domagk’s discovery—after so many years of fruitless searching for specific antibacterial agents—was received with a great deal of skepticism. In 1936 L. Colebrook and M. Kenny of the British Medical Research Council confirmed Domagk’s findings and concluded that “the clinical results together with the mouse experiments support the view that... there is more hope of controlling these early streptococcal infections by the administration of this or some related chemotherapeutical agent than by any other means at present available.” In the first paper on prontosil published in the United States, P. H. Long and E. A. Bliss mentioned Domagk only as one of the investigators of prontosil, but in the same issue of the Journal of the American Medical Association, its editor gave Domagk full credit for his significant paper and hoped that “further investigations will disclose a definite group of disorders characterised by high virulence and mortality which can be materially helped by appropriate chemotherapy.” Their hopes were indeed fulfilled, but only after workers at the Pasteur Institute in Paris—the Tréfuëls, F. Nitti, D. Bovet, and E. Fourneau—had established that the azo component of prontosil dissociated in vivo and that the liberated sulfonamide radical was responsible for the antibacterial effect. This was a very important discovery, because sulfonamide could be produced far more cheaply than prontosil.
Ironically enough, at that very time an agar plate containing an even more powerful antibacterial agent—penicillin—lay forgotten in St. Mary’s Hospital in London. Its owner, Alexander Fleming, had become highly interested in prontosil and the sulfonamide derivatives that followed, but in his many papers on antibacterial and antiseptic treatment published between 1938 and 1940 he never mentioned penicillin, the antistaphylococcal action of which he had first observed in 1928.
In 1938 L. E. H. Whitby synthesized sulfapyridine, which soon became the drug of choice in the treatment of the pneumococcal pneumonias. Many other sulfa drugs followed in quick succession. The structural formulas of the most important ones are shown in Figure 1.
Domagk’s discovery profoundly changed the prognosis of many dangerous and potentially fatal diseases such as puerperal fever, erysipelas, cerebrospinal meningitis, and pneumonia.
In October 1939, sponsored by American, French, and British scientists, Domagk was awarded the Nobel Prize in physiology or medicine. He duly acknowledged the great honor to the rector of the Caroline Institute; but some weeks later, after having been arrested by the Gestapo, he declined the prize in a letter drafted for him by the German authorities. (After the peace prize had been awarded in 1936 to the German radical and pacifist writer Carl von
Ossietzky, who was a prisoner in a concentration camp, Hitler had forbidden any German to accept a Nobel Prize.) Domagk eventually received the Nobel Prize medal (1947), but by then the prize money had been redistributed. He received many other high honors and an honorary professorship of the University of Valencia, and he became doctor honoris causa of many European and American universities. He was especially pleased by the award of the Paul Ehrlich Gold Medal and the Cameron Medal of Edinburgh and by his election as a foreign correspondent of the Royal Society of London.
The discovery of the sulfonamides reawakened interest in the sulfones, the derivatives of 4, 4′-diaminodiphenyl-sulfone (DDS) (Fig. 2). Because of their high toxicity the sulfones had never been favored in the treatment of acute bacterial infections, but in 1941, E. V. Cowdry and C. Ruangsiri reported encouraging effects in treating rat leprosy with a DDS derivative, sodium glucosulfone. After G. H. Faget and his co-workers confirmed this in a clinical trial in 1943, the sulfones largely replaced the venerable chaulmoogra oil in the treatment of human leprosy and revolutionized the prognosis of this biblical scourge.
After World War II, with the antibiotics having
joined the therapeutic armamentarium against acute bacterial diseases, Domagk’s interests shifted to the chemotherapy of tuberculosis. The euphoria induced by the discovery of streptomycin had by that time given way to considerable disillusionment because of the rapidly increasing numbers of streptomycinresistant strains of the tuberculosis mycobacterium.
Together with R. Behnisch, F. Mietzsch, and H. Schmidt, Domagk reported in 1946 on the tuberculostatic action in vitro of the thiosemicarbazones of which the 4′-acetyl-aminobenzaldehyde (Conteben, Tibione) seemed to be the most promising compounds. Because of their many and dangerous toxic side effects the thiosemicarbazones never became popular in clinical medicine, but for many years they were used as “second-line drugs” against mycobacteria that were resistant to one or more of the standard antituberculous drugs.
The work of Domagk and his colleagues with the thiosemicarbazones resulted, however, in a supremely important accidental discovery. In 1945 V. Chorine had reported on the tuberculostatic action of the nicotinamides, and his findings were rediscovered by D. McKenzie, L. Malone, S. Kushner, J. J. Oleson, and Y. Subba Row in 1948. This produced no practical results until it became known that the active agents of the nicotinamides were derivatives of isonicotinic acids. In 1951 H. H. Fox tried to prepare isonicotinaldehyde-thiosemicarbazone. An intermediate product, isonicotinoylhydrazine (isoniazid), was tested in New York’s Sea View Hospital in 1952 and has since become one of the most potent and reliable drugs in the treatment of tuberculosis.
Finally Domagk turned to the greatest challenge of all, the chemotherapy of cancer. He experimented mostly with ethylene-iminoquinones, but success evaded him as it did so many other workers in that field. In a letter quoted by Colebrook he wrote: “One should not have too great expectations of the future of cytostatic agents.”
It is characteristic of Domagk’s intensive scientific curiosity and humane outlook that he wrote at the end of his life: “If I could start again, I would perhaps become a psychiatrist and search for a causal therapy of Mental Disease which is the most terrifying problem of our times.”
The dawn of the new chemotherapeutic era in Germany was no accident, if only for the traditional close association between the chemical industry and medical research in that country. Nevertheless, twenty-seven years passed between P. Gelmo’s first preparation of a sulfonamide in 1908, during Ehrlich’s lifetime, and its recognition by Domagk as an elixirium magnum sterilisans. Gelmo’s original paper, “Sulphamides of P-aminobenzene Sulphonic Acid,” is in Journal für praktische Chemie, 77 (1908), 369–382.
Domagk was fortunate in having adequate chemical help, the lack of which prevented Fleming from advancing with penicillin for eleven years. But here, as in so many similar situations, Pasteur’s famous dictum applies: “The lucky chance favors only the prepared mind.”
I. Original Works. Domagk’s writings are “Untersuchungen über die Bedeutung des retikuloendothelialen Systems für die Vernichtung von Infektionserregern und für die Enstehung des Amyloids,” in Virchows Archiv für pathologische Anatomie und Physiologic und für klinische Medizin, 253 (1924), 594–638; “Ein Beitrag zur Chemotherapie der bakteriellen Infektionen,” in Deutsche medizinische Wochenschrift, 61 (1935), 250–253; “Über eine neue, gegen Tuberkelbazillen in vitro wirksame Verbindungsklasse,” in Naturwissenschaften, 33 (1946), 315, written with R. Behnisch, F. Mietzsch, and H. Schmidt; Pathologische Anatomie und Chemotherapie der Infektions-Krankheiten (Stuttgart, 1947); “Investigations on the Anti-tuberculous Activity of the Thiosemicarbazones in vitro & in vivo,” in American Review of Tuberculosis and Pulmonary Diseases, 61 (1950), 8–19; “Chemotherapy of Cancer by Ethylenimino-quinones,” in Annals of the New York Academy of Sciences, 68 (1957–1958), 1197–1204; and “Über 30 Jahre Arzt,” in Therapie der Gegenwart, 102 (1963), 913–917.
II. Secondary Literature. Writings on Domagk or his work are V. Chorine, “Action de l’amide nicotinique sur les bacilles du genre mycobacterium,” in Comptes rendus hebdomadaires des séances de l’Académie des sciences, 220 (1945), 150–151; L. Colebrook, “Gerhard Domagk,’r in Biographical Memoirs of the Royal Society, 10 (1964), 39–50; L. Colebrook and M. Kenny, “Treatment of Human Puerperal Infections and Experimental Infections in Mice with Prontosil,” in Lancet (1936), 1 , 1279–1286; E. V. Cowdry and C. Ruangsuri, “Influence of Promin, Starch and Heptaldehyde on Experimental Leprosy in Rats,” in Archives of Pathology, 32 (1941), 632–640; G. H. Faget et at., “The Promin Treatment of Leprosy, a Progress Report,” in Public Health Reports, 58 (1943), 1729–1741; E. Fourneau et al,. “Chimiothérapie des infections streptococciques par les dérivés du p-aminophénylsulfamide,” in Comptes rendus des séances de la Société de biologie122 (1936). 652–654; H. H. Fox, “The Chemical Attack on Tuberculosis,” in Transactions of the New York Academy of Sciences, 15 (1952), 234–242; L. S. Goodman and A. Gilman, The Pharmacological Basis of Therapeutics (New York, 1960), pp. 1250–1300.
See also H. Hörlein, “Chemotherapy of Infectious Diseases Caused by Protozoa and Bacteria,” in Proceedings of the Royal Society of Medicine, 29 (1936), 313–324; editorial in Journal of the American Medical Association, 108 (1937), 48–49; P. H. Long and E. A. Bliss, “Para-Amino-Benzene-Sulfonamide and Its Derivatives,” ibid., pp. 32–37; D. McKenzie et al., “The Effect of Nicotinic Acid-amide on Experimental Tuberculosis of White Mice,” in Journal of Laboratory and Clinical Medicine, 33 (1948), 1249–1253 I. J. Selikoff et al., “Chemotherapy of Tuberculosis With Hydrazine Derivatives of Isonicotinic Acid,” in Quarterly Bulletin of Sea View Hospital (New York), 13 (1952), 27 T. L. Sourkes, Nobel Prize Winners (New York, 1967), pp. 214–219; O. Warburg, “Gerhard Domagk,” in Deutsche medizinische Wochenschrift, 90 (1965), 34, 1484–1486 L. E. H. Whitby, “Chemotherapy of Pneumococcal and Other Infections With 2- (p-aminobenzenesulfonamide) pyridine,” in Lancet (1938), 1 , 1210–1212.