1932

Sulfanilamide

Ernest Fourneau (1872–1949), Gerhard Domagk (1885–1964), Fritz Mietzsch (1896–1958), Josef Klarer (1898–1953), Daniel Bovet (1907–1992)

People remember penicillin as the antibiotic “wonder drug,” but the sulfa drugs, particularly sulfanilamide, were there first, and they created a sensation when they were discovered.

That discovery was not straightforward. German pathologist and bacteriologist Gerhard Domagk and his team, chemists Josef Klarer and Fritz Mietzsch, at German pharmaceutical giant Bayer had noticed how some dye molecules stained bacteria, and thought that there must be something about their structures that targeted the bacterial membranes. A search through hundreds of dyes (and related compounds) turned up a bright red one, in 1932, that showed weak activity in mice. This lead structure was modified into a series of analogs, one of which was truly potent. After human tests, it came on the market as Prontosil, the first broad-spectrum antibiotic ever found. But it worked only in people and animals; it did not kill bacterial cultures in the lab, although it did stain them red.

It would stain other things as well. During this testing period, Domagk’s daughter, Hildegarde, became dangerously ill with a streptococcal infection from an accident with an embroidery needle. He gave her a large dose of Prontosil, which saved her arm and probably her life, but at the cost of staining her skin with a reddish hue that never disappeared. A French research team led by chemists Ernest Fourneau and Daniel Bovet shorly discovered that Prontosil was not the real drug. It was being cleaved inside the body to a much smaller active compound, sulfanilamide, which was cheap (and colorless, so the staining side effect was never a problem again). Sulfanilamide went into immediate use, followed swiftly by countless derivatives and analogs. “Sulfa” was the frontline antibiotic of World War II and was given to Winston Churchill during a bout of pneumonia, but bacteria were already starting to develop resistance to the whole class of drugs, due to the survival advantage of mutant enzymes that sulfanilamide did not inhibit.

Domagk was awarded the Nobel Prize in Physiology or Medicine in 1939, but he was arrested by the Gestapo for attempting to accept it. He finally got his medal in 1947.

A tube of Prontosil tablets, the first commercial “sulfa” antibacterial drug, which became available in the 1930s.