Gerhard Domagk developed the experimental procedures for testing the effectiveness of drugs and discovered that sulfonamides are effective in curing a large number of diseases caused by bacteria.
Quinine was used to treat malaria for hundreds of years and had been purified by the French chemists Pierre Joseph Pelletier and Joseph Bienaimé Caventou around 1820. Nevertheless, Paul Ehrlich is usually credited with being the father of modern chemotherapy because he was responsible for discovering a number of useful drugs. Ehrlich was familiar with dyes used to stain microorganisms and suspected that some of them might specifically poison the microorganisms responsible for disease but not hurt the patient. He began a search of dyes
Ehrlich and his coworkers also synthesized hundreds of organic compounds that contained arsenic. In 1910, he found that one of these compounds, later named Salvarsan,
In 1915, tartar emetic (a compound containing the metal antimony) was found to be useful in treating kala-azar, a disease caused by a protozoan. Kala-azar affected millions of people in Africa, India, and Asia, causing much suffering and many deaths each year. Two years later, it was discovered that injection of tartar emetic
Gerhard Domagk had been trained in medicine but turned to research in an attempt to discover chemicals that would inhibit or kill microorganisms. He became director of experimental pathology and bacteriology at the Elberfeld laboratories of the German chemical firm I. G. Farbenindustrie in 1927. Ehrlich’s discovery that trypan dyes selectively poisoned microorganisms suggested to Domagk that he look for antimicrobials in a new group of chemicals known as azo dyes. A number of these dyes were synthesized from sulfonamides and purified by Fritz Mietzsch and Josef Klarer. Domagk found that many of these dyes protected mice infected with the bacteria Streptococcus pyogenes. In 1932, he discovered that one of these dyes was much more effective than any tested previously. This red azo dye containing a sulfonamide was named prontosil rubrum.
From 1932 to 1935, Domagk began a rigorous testing program to determine the effectiveness and dangers of prontosil at different doses in animals. Given that all chemicals injected into animals or humans are potentially dangerous, Domagk set about determining the doses that would harm or kill. In addition, he worked out the lowest doses that would eliminate the pathogen. The ratio of the smallest amount of drug that kills the patient to the minimum amount of drug that eliminates the pathogen is called the therapeutic ratio of the drug. Chemicals with low therapeutic ratios (near one) are not very useful; those with high therapeutic ratios (greater than ten) are usually the safest and the most effective drugs. The firm supplied samples of the drug to a select number of physicians to carry out clinical trials on humans. Animal experimentation can only indicate which chemicals might be useful in humans and what doses are required.
The synthesis and purification of a drug, its testing in animals, and then its testing in humans require the involvement of many scientists and technicians as well as expensive and appropriate facilities. Clearly, the discovery of a new group of useful drugs does not result from the discovery and work of a single person. The chemists, the animal researchers, and the physicians at clinics all contribute to the final conclusions.
From drug testing in animals, Domagk learned what doses were effective and safe. This knowledge saved his daughter’s life. One day while knitting, Domagk’s daughter punctured her finger with a needle and infected herself with virulent bacteria. The bacteria quickly multiplied and spread from the wound into neighboring tissue. In an attempt to alleviate the swelling, the infected area was lanced and allow to drain. This did not stop the infection that was spreading into her lymph and blood, however. The child became critically ill because of the developing septicemia (blood poisoning). In those days, more than 75 percent of those who acquired blood infections died. Domagk realized that the chances for his daughter’s survival were very poor. In desperation, he obtained some of the powdered prontosil that had worked so well on infected animals. He extrapolated from his animal experiments how much to give his daughter so that the bacteria would be killed but his daughter would not be poisoned. Within hours of the first treatment, her fever dropped. Complete recovery followed repeated oral doses of prontosil. Domagk’s daughter was saved.
In 1935, Domagk published his results demonstrating that prontosil was useful in treating streptococcal infections in animals. German physicians, who had extensively tested prontosil on humans, reported that it was also extremely effective in treating streptococcal infections in humans. This announcement was an important first step in the battle against diseases caused by bacteria. Different strains of Streptococcus pyogenes are responsible for strep throat, rheumatic fever, scarlet fever, erysipelas (a spreading skin infection), cellulitis (a localized skin infection), puerperal sepsis (childbed fever), and septicemia. During the 1920’s, puerperal sepsis, rheumatic fever, scarlet fever, and septicemia killed thousands of women, babies, and children every year.
The use of sulfonamides lowered the death rates of a number of diseases very quickly. Before 1935, the death rate for puerperal sepsis in England was 175 per 100,000 births. In 1937 and 1938, the rate fell to 80 per 100,000. The use of sulfanilamides saved the lives of more than one thousand English mothers in only two years.
The publication of Domagk’s 1935 paper stimulated extensive research in Germany, France, and England. French researchers found that the active portion of the azo dye prontosil was the colorless sulfonamide called sulfanilamide. Much later, it was discovered that bacteria are sensitive to prontosil if they are able to cleave the azo dye and release sulfanilamide. Sulfanilamide, as well as other sulfonamides, blocks the synthesis of a coenzyme bacteria needed to grow. The discovery that sulfanilamide was the actual antimicrobial agent spurred scientists to synthesize new classes of sulfonamides and test their effectiveness on other pathogenic bacteria.
Domagk demonstrated that some sulfonamides called ulirons were effective against the bacteria that caused gonorrhea. The ulirons were the first drugs used in Germany to treat gonorrhea because prontosils were not effective. Soon after the introduction of ulirons, it was found that gonorrhea could be treated more effectively with a number of newly synthesized sulfonamides. By 1938, English researchers and physicians demonstrated that sulfapyridine was effective against a number of bacterial pathogens. It was used to treat gonorrhea, pneumonia, meningitis, and wound infections. Another sulfonamide called sulfathiazole was even more effective against these organisms. Because of its rapid excretion, sulfathiazole was replaced by sulfadiazine and sulfadimidine.
Research on the many different sulfonamides and their effectiveness on bacterial infections showed that bacterial species varied significantly in their sensitivity to a particular sulfanilamide. For example, some gonococci (bacteria that cause gonorrhea) were sensitive and effectively inhibited by low concentrations of a sulfonamide. Other bacteria of the same species were extremely resistant and would grow even when subjected to very high concentrations of the sulfonamide. It was found that a particular bacterium was not inhibited equally by all the different sulfonamides. Sulfathiazole, for example, might be more effective than sulfapyridine, which in turn might be more effective than uliron. Experiments showed that a particular sulfonamide was not equally effective when tested on different genera. For gonococcal infection, sulfathiazole was found to be the best sulfonamide. Nevertheless, sulfapyrimidines and sulfones were discovered to be more effective for streptococcal infections.
In 1940, Domagk observed that sulfathiazole and sulfathiodiazole inhibited the bacterium Mycobacterium tuberculosis that causes tuberculosis. In 1946, Domagk and the chemists working with him reported the development of a new group of compounds called thiosemicarbazones that were also effective against the mycobacteria that caused tuberculosis. Treatment of tuberculosis with the semicarbazones required more than one hundred days at a dose of one gram a day. The use of sulfonamides and semicarbazones beginning in 1945 caused a dramatic decline in the number of cases and deaths caused by tuberculosis. Because mycobacteria frequently develops resistance if treated with only one drug, tuberculosis is now treated with a combination of drugs that include streptomycin (1947), para-aminosalicylic acid (1950), isoniazid (1952), and rifampin (1963). Dapsone, a sulfone studied by Domagk, is used to treat leprosy (Hansen’s disease), which is caused by Mycobacterium leprae.
Domagk’s work also showed that sulfonamides were effective in treating gas gangrene caused by the anaerobic bacteria Clostridium septicum, C. perfringens, and C. novyi. Sulfonamides were not very useful in treating tetanus even though Clostridium tetani was inhibited. This results from the fact that the disease is caused by a toxin that binds to nerve cells. Killing the bacteria with sulfonamides after the toxin has caused its damage is like closing the barn door after the horses have escaped. A new sulfonamide, resembling sulfanilamide, was shown to be more effective on the clostridia than sulfanilamide, uliron, or sulfathiazole.
Spread on wounds and taken orally, sulfonamides saved thousands of lives during World War II. For example, the U.S. Army lost 8.25 percent of its wounded in World War I, but in World War II, thanks largely to the use of sulfonamides, the proportion of wounded who died was cut to 4.5 percent. The proportion of fatalities resulting from operations on perforated appendixes fell from 14 percent to 1 percent when sulfonamides were used.
Although Domagk was awarded the 1939 Nobel Prize,
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Brock, Thomas D., ed. Milestones in Microbiology. 1961. Reprint. Washington, D.C.: American Society for Microbiology Press, 1998. Collection of original papers by scientists who contributed to the development of microbiology. Part 5 is concerned with chemotherapy. Papers by Ehrlich, Sir Alexander Fleming, and Domagk are worthwhile reading. -
Edwards, David I. Antimicrobial Drug Action. Baltimore: University Park Press, 1980. Concise, clearly written resource for those interested in antimicrobial drugs. Includes a short history of antimicrobial chemotherapy, but most discussion is devoted to how the drugs inhibit and kill microorganisms as well as how microorganisms become resistant to drugs. Features a section on chemotherapeutic agents used to treat some cancers. -
Franklin, T. J., and G. A. Snow. Biochemistry and Molecular Biology of Antimicrobial Drug Action. 6th ed. New York: Springer, 2005. Presents a concise history of the discovery of antimicrobial agents. Includes discussion of the mechanism of action of the sulfonamides. -
Silverstein, Arthur M. Paul Ehrlich’s Receptor Immunology: The Magnificent Obsession. New York: Academic Press, 2001. Focuses on Ehrlich’s many contributions to the field of immunology, placing them in the context of their times. Includes appendixes and indexes. -
Taylor, F. Sherwood. The Conquest of Bacteria: From Salvarsan to Sulphapyridine. New York: Philosophical Library, 1942. A history for the general reader of drug development before antibiotics were developed in the 1940’s. Focuses on the discoveries that different sulfonamides were effective on a variety of pathogenic bacteria. Makes clear the roles played by Domagk and other researchers in the discovery of the effectiveness of the sulfonamides.
Plague Kills 1.2 Million in India
Ehrlich Introduces Salvarsan as a Cure for Syphilis
Fleming Discovers Penicillin in Molds
Florey and Chain Develop Penicillin as an Antibiotic