The advent of the sulfa drugs in the mid-1930s gave physicians a powerful weapon.

Gerhard Domagk, sulfa drug pioneer. NATIONAL LIBRARY OF MEDICINE/J. F. LEHMANN

In the United States in the early 1930s, about 100,000 people died annually from pneumonia, more than from any other infectious disease. Half or more of the patients who became ill from cerebrospinal meningitis did not recover. More than 2000 mothers died in childbirth annually from puerperal sepsis, a blood poisoning commonly known as childbed fever. Gonorrhea, a debilitating and painful ailment that was difficult to treat and could lead to chronic damage to the body, afflicted some 12 million Americans.

By the early 1940s, death rates from all these—as well as several other serious bacterial infections—had decreased dramatically. Much of the credit for this remarkable reversal in mortality goes to two German chemists and a pathologist who synthesized and clinically evaluated the first of the sulfonamides, a group of drugs that would open the door to modern medicines.

The sulfa drugs were not the first chemicals to be used to treat disease. In the early 20th century, a few were prescribed, with limited success, against urinary infections. A breakthrough came in 1909, when the renowned German medical researcher Paul Ehrlich, after several years of painstaking research beginning in 1903 on organoarsenic compounds, found that his compound 606, arsphenamine, was effective against the trypanosomes that cause syphilis. Marketed by the German firm Hoechst with the trade name Salvarson, Ehrlich’s “magic bullet” launched a medical practice that Ehrlich called chemotherapy. Later, another chemical product, Atabrine, was found to be useful for treating malaria.

Syphilis and malaria are caused by protozoa, however; no drugs were available for treating bacterial (or viral) diseases—at least without doing grievous harm to the patient, as well as the microbe.

In 1927, the giant German chemical cartel I.G. Farbenindustrie decided to screen for medical activity the various dyestuffs that it was developing. It hired Gerhard Domagk to take charge of the project. After service in the German army during World War I, Domagk had earned an M.D. from the University of Kiel in 1921. He taught pathology at two German universities before joining Farben.

Domagk turned his attention to azo dyes, so called because the two major parts of the molecule are linked by a double bond between two nitrogen atoms. Some of these dyes attach strongly to protein in fibers or leather, so that they hold fast against fading or cleaning. Domagk reasoned that they might also attach themselves to the protein in bacteria, inhibiting if not killing the organisms.

In 1932, two chemists working for Farben, Fritz Mietzsch and Josef Klarer, synthesized a new orange-red dye, sulfamidochrysoidine. Mietzsch earlier had played a key role in preparing the first antimalarial drug, Atabrine. Testing the new dye on laboratory rats and rabbits infected with streptococci bacteria, Domagk found that it was highly antibacterial but not toxic. It was named Streptozan but soon changed its name to Prontosil.

When Prontosil was first used on a human patient is not quite clear. One report has it that a Düsseldorf physician obtained a sample in 1933 and, in an act of desperation, administered two doses to a 10-month-old boy who was dying of staphylococcal septicemia; the baby made an unexpectedly rapid recovery. Another account is that Domagk himself used Prontosil to treat his own daughter, who was deathly ill from a streptococcal infection following a pin prick. Whatever the case, clinical tests with the drug were a resounding success.

Strangely, Domagk did not immediately publish his remarkable lab results. His landmark paper of February 1935, shortly after Farben had obtained a patent on the product, won wide attention in Europe. Domagk was awarded the Nobel Prize in Physiology or Medicine in 1939, but the Nazi government, at odds with the Nobel Committee, refused to let him accept it; he eventually received his medal after World War II in 1947. He later worked on the chemotherapy of tuberculosis and cancer before he died in 1964 at the age of 68.

A French research team at the Pasteur Institute in Paris was struck by two unusual aspects of Prontosil. First, it is active in vivo but not in vitro. Second, patients treated with the drug do not excrete it; rather, they excrete a simpler molecule, sulfanilamide, which constitutes about half the dye molecule. The French scientists concluded that Prontosil is cleaved at its nitrogen–nitrogen double bond when ingested; lab experiments soon showed that sulfanilamide (p-aminobenzenesulfonamide) is every bit as medically active as Prontosil itself. It acts not by killing the invading bacteria, but by inhibiting their reproduction, so that the body’s natural defense system can take charge.

The French observation was significant. Sulfanilamide was first reported by the Austrian chemist Paul Gelmo, who had synthesized and characterized it for his doctoral dissertation in 1908. It was used as a dye intermediate, but its potent therapeutic properties unfortunately went unrecognized. The patent on it had long expired. Thus, anyone was free to make and use it. Moreover, it was appreciably less expensive to make than Prontosil.

Doctors in England in 1936 had stunning results using the new drug to treat childbed fever and meningitis. Tests in the United States in 1936, initially at Johns Hopkins Hospital in Baltimore, MD, and Western Pennsylvania Hospital in Pittsburgh, showed that it was also effective against various streptococcic infections and pneumonia. Prontosil won wide publicity in the United States in 1936 when it was used to treat President Franklin Delano Roosevelt’s son Franklin, Jr., who was severely ill from a streptococcic infection.

Soon pharmaceutical firms throughout Europe and the United States were trying to develop improved sulfa drugs. More than 5000 such compounds were prepared in the late 1930s and early 1940s. Only a handful proved of medical value. Among them, sulfapyridine was used against pneumonia (it was used to treat Winston Churchill when he came down with pneumonia during World War II); sulfathiazole was used against both pneumonia and staphylococcal infections; sulfadiazine was used against pneumonococcal, streptococcal, and staphylococcal bacteria; and sulfaguanadine against dysentery.

Use spread rapidly. Output of sulfa drugs in the United States in 1937—the first year of real commercial production—totaled about 350,000 pounds; by 1940, it had more than doubled. By 1942, it topped an estimated 10 million pounds.

But widespread demand brought tragedy. Deciding that many people would prefer a liquid form of the drug rather than the usual pill or injection, in 1937, S. E. Massengill Co., a small drug formulator in Bristol, TN, mixed up an “Elixir of Sulfanilamide”. For unclear reasons, the solvent used was diethylene glycol. Massengill made no tests on its elixir before shipping it from its plant. Diethylene glycol is very toxic. First news of deaths was from Tulsa, OK; reports quickly followed from throughout the South and Midwest. In all, 108 people died, largely from kidney and liver failure. One final death, by suicide, was the ill-informed chemist who had formulated the elixir.

Under the U.S. food and drug law then in place, the government seized Massengill’s deadly mixture only because it was misbranded; “elixir” implied that the solvent in the bottle was ethyl alcohol. Drug dispensers were required by law to label their products accurately but not to test them for safety. The company was fined $16,800 for its false label.

The lethal concoction did encourage, however, enactment of a much-strengthened food and drug law that was then pending in Congress. The Federal Food, Drug, and Cosmetics Act of 1938, which overhauled the law of 1906, stipulated that manufacturers must test any new drug for safety and report the results to the U.S. Food and Drug Administration.

During World War II, U.S. troops were issued sulfa drug tablets to take if they were wounded. The use of the drugs to fight dysentery allowed U.S. forces to overcome a disease that at times severely hampered the Japanese fighting in the South Pacific.

By the end of the war, though, sulfa drugs were largely eclipsed by penicillin and, later, by other antibiotics. Sulfonamides had serious drawbacks. Because of their typical low solubility, they could be deposited in the kidney and cause damage to it. Also, bacteria tend to build up a resistance to them, making them ineffective.

Sulfa drugs still play a role in modern medicine, albeit relatively minor. They are prescribed, for example, for treating urinary tract, vaginal, and eye infections, as well as for veterinary applications.

During the decade or so after their introduction, however, they saved tens of thousands of lives. And they ushered in the era of modern chemotherapy by spurring research on many other antimicrobial drugs.

David M. Kiefer, former assistant managing editor of Chemical & Engineering News until his retirement in 1991, is a consulting editor for Today’s Chemist at Work. Send your comments or questions regarding this article to tcaw@acs.org or the Editorial Office 1155 16th St N.W., Washington, DC 20036.