The Demon Under the Microscope

The Demon Under The Microscope: From Battlefield Hospitals to Nazi Labs, One Doctor's Heroic Search for the World's First Miracle Drug by Thomas Hager, Crown, 2007. 

Sulfa Drugs

This is an excellent history of the rise of synthetic antibiotics. Unlike penicillin, which is a natural product of mold, the sulfa drugs were created from scratch in the laboratory. The German chemists took the lead. They had already developed synthetic dyes. They experimented with using these dyes to kill bacteria.

Gas Gangrene

A major motivation for this work was the large amount of gas gangrene from battlefield wounds in the First World War. Gas gangrene was caused by Streptococcus infected wounds. 

Chemists and Biologists

The research teams had two parts, chemists who synthesized experimental drugs, and biologists who tested them in mice. Gerhard Domagk was the biologist. Josef Klarer and Fritz Mietzsch were the chemists. Heinrich Hörlein at Bayer was the one who hired Domagh. 

Azo Dyes

They experimented with derivatives of azo dyes. Azo dyes have two aromatic rings connected by a bridge of two double bonded nitrogen atoms (N=N). A derivative is a molecule where the original molecule has another molecule, called a substituent, attached to it. One of the substituents they tried was sulfanilamide, a common chemical in the chemistry industry. Domagk tested it in mice that had been infected with Streptococcus bacteria, and the mice lived.

Prontosil

Bayer patented this first “sulfa” drug and called it Prontosil. The German scientists believed that the azo dye part of the combined molecule was the part that killed bacteria. 

Pasteur Institute

Bayer gave a sample of Prontosil to the Pasteur Institute. That sulfanilamide without the azo dye worked just as well discovered by the French scientists at the Pasteur Institute: Ernest Fourneau, Federico Nitti, Filomena Nitti, Jacques and Thérèse Trëfouël, and Daniel Bovet. 

Other Sulfa Drugs

Other sulfa drugs were soon developed, and were proven effective against many other infectious diseases, including pneumonia, Meningitis, staphylococcal infections, urinary tract infections gonorrhea, and trachoma. Mechanism of action: Sulfanilamide is a competitive inhibitor of the bacterial enzyme that binds para-aminobenzoic acid in order to synthesize the folate vitamin (B9).