Sulfa drugs, developed in the 1930s, were the first medications effective against bacterial disease. They appeared as the first "miracle drugs" at a time when death from bacterial infections such as pneumonia and blood poisoning were common.
In 1932, German physician and biomedical researcher Gerhard Domagk was working on a project for the German industrial giant I. G. Farbenindustrie to test industrial chemicals for medical utility. One of the chemicals was a dye called Prontosil, or sulfamidochrysoidine. Domagk hypothesized that since the dye worked by binding to the proteins in fabric and leather, it might also bind to the proteins in bacteria , thus inhibiting their action. Experiments on laboratory animals infected with streptococcus were promising, and were soon followed by successful clinical tests.
In 1936, Prontosil was successfully used against puerperal sepsis, or "childbed fever," which was killing thousands of mothers every year. It was also shown to be effective against meningitis , pneumonia, and streptococcal infections.
Meanwhile, scientists at the Pasteur Institute in Paris discovered that upon ingestion, the dye molecule was cleaved in two, and that the active part, sulfanilamide, was just as effective on its own. This was important because the smaller molecule was not covered by Farben's patent on Prontosil, and was also less expensive to produce.
There followed a rush by pharmaceutical companies in the United States and Europe to develop sulfa drugs of their own. Among the most effective were sulfapyridine for pneumonia, sulfathiazole against pneumonia and staphylococcus, sulfaguanadine to treat dysentery , and sulfadiazine, which worked against pneumonia, strep and staph. Domagk was awarded the Nobel Prize in Medicine in 1939, but World War II prevented him from receiving his medal until 1947.
Investigating the action of the sulfa drugs led to an important new understanding of the action of pharmaceuticals. Sulfanilamides compete with the action of para-aminobenzoic acid (PABA), which bacteria use to produce folic acid. Without folic acid, the bacteria cannot synthesize DNA . This is an example of a common drug mechanism called antagonism. A structurally similar molecule can work against a substance necessary to the metabolism of a microorganism (or involved in some other disease process) by competitively binding to the same enzyme and thus blocking its action.
A tragic episode involving a sulfa drug was also important in medical history because of its effect on United States law. In 1937, the S. E. Massengill Company released a sulfa medication in liquid form. Unfortunately, a toxic solvent (the medium suspending the sulfa medication) was used, and more than 100 people died. The next year, the Federal Food, Drug and Cosmetics Act was passed, requiring that new drugs be tested for safety.
The ability to fight dysentery and other bacterial diseases with sulfa drugs was important to soldiers in World War II. However, too much sulfa was bad for the kidneys, and by the end of the war, penicillin and other newly developed antibiotics with fewer side effects became increasingly available and preferred in treatment. In addition, many bacterial strains have developed resistance against sulfa drugs in the decades since they were developed, which has also limited their usefulness. Regardless, they are still effective against some infections, including leprosy , and are often used in developing nations because of their low cost.
See also Antibiotic resistance, tests for; Antibiotics; Bacteria and bacterial infection; Bioterrorism, protective measures; History of the development of antibiotics; History of public health; Infection and resistance; Penicillin; Streptococci and streptococcal infections
Sulfa drugs were the first synthetic drugs with widespread antibiotic activity to be put into clinical use. In the 1930s German chemists observed that certain dyes used to stain bacteria stopped microbial growth. Gerhard Domagk, a pathologist at I. G. Farbenindustrie, performed a series of experiments on mice infected with streptococcus bacteria and observed that mice injected with an orange-red dye called Prontosil survived bacterial infection. Prontosil is an azo dye that had not shown antibacterial activity during earlier in vitro tests. However, in vivo , the dye is transformed into sulfanilamide, a compound with antimicrobial activity (see Figure 1). Domagk had such faith in Prontosil's anti-infectious properties that he is reported to have injected the dye into his daughter when she had septicemia. In 1939 Domagk was awarded the Nobel Prize in physiology or medicine for his discovery.
Once sulfanilamide was recognized as an active antimicrobial agent, scientists synthesized thousands of sulfonamides to test for bactericidal activity. It was later realized that sulfonamides do not actually kill bacteria; they interfere with bacterial growth and replication. Sulfa drugs are bacteriostatic. They inhibit an enzyme necessary for the biosynthesis of folic acid in bacteria. Folic acid is necessary for the biosynthesis of thymine and the purine bases, the building blocks of DNA . Bacteria that are sensitive to sulfa drugs are unable to acquire folic acid from their environment and, in the presence of sulfonamides, are unable to synthesize the folic acid essential for cell growth and multiplication. Sulfonamides do not harm their human hosts, however, because, unlike susceptible bacteria, humans acquire folic acid from their diet and lack the enzyme necessary for synthesizing folic acid.
see also Allosteric Enzymes; Antibiotics; Inhibitors; Penicillin.
Nanette M. Wachter
American Chemical Society (2000). The Pharmaceutical Century: Ten Decades of Drug Discovery. Washington, DC: ACS.
Williams, David A., and Lemke, Thomas L. (2002). Foye's Principles of Medicinal Chemistry, 5th edition. Baltimore: Lippincott Williams & Wilkins.
Wolff, Manfred E., ed. (2003). Burger's Medicinal Chemistry and Drug Discovery, 6th edition. New York: Wiley.