The Penicillin before Penicillin

We who live in the era of so many effective antibiotics would find it hard to imagine an era when even a simple cut or abscess would lead to a frequently fatal condition. It's hard to imagine the distress of doctors and family members when they saw a patient simply die of such an apparently minor affliction. The story of penicillin which finally emerged to fight these infections has become the stuff of legends. What's probably still living in the shadows is the equally crucial discovery of sulfa drugs which were the penicillins of their time; perhaps not as effective, but almost miraculous by virtue of being the first.

Now Thomas Hager has come out with a book that should rescue the heroic stories from being forgotten. Hager is a fine writer, and I have read his comprehensive biography of Linus Pauling. He now has written 'The Demon under the Microscope', a history of sulfa drugs discovered by German chemists in the 1920s and 30s. The New York Times gave it a favourable review, and I am looking forward to reading it. The NYT reviewer compared it to 'Microbe Hunters' a classic which has inspired many famous scientists including Nobel laureates in their childhood. I was also quite intrigued by the book, which reads like a romantic account of microbiology. Of course, truth is always harsher than such accounts, but it does no harm to initiate a child into science with them.

It was interesting for me to read that the German chemists had taken out a patent on the azo part of the first sulfa drug. They did not know that in fact it was the sulfa part which confered activity, and they were soon scooped by French chemists who actually discovered that even sulfanilamide alone has potency.

Sulfa drugs of course inihibit dihydrofolate reductase which is involved in nucleotide synthesis, and they are quite close to the ideal of the 'magic bullet', a molecule that is potent, has few to zero side effects, and most importantly, is selective for the microorganism. In this case, dihydrofolate enzyme is expressed only in bacteria. That does not necessarily mean that there will be no human side effects- after all, every molecule can target more than one protein- but it seems to work well in this particular case. Sulfa drugs led to further research on DHFR, which also led to the Methotrexate, a compound that is even today a standard component of anti-cancer therapy.