Infection and its control: antibiotics

Part 4

In the last third of the 19th century, the Germ Theory of Disease was a liberating idea that helped extract medicine from near futility. In veterinary medicine, the anthrax vaccine protected sheep and cattle. In public health, then called The Sanitarian Movement, bacteria and other contaminants in water or food could be detected and analyzed. The effects of good nursing, espoused by Florence Nightingale in the 1850s and after, could be explained in terms of bacteria or viruses killed. The first great medical application was the antiseptic surgery pioneered by Joseph Lister. 

Yet the idea of bacteria (and later viruses) causing disease did not come easily. The Sanitarians rejected it, as did Florence Nightingale (vehemently), and most of the physicians of the time. They thought in terms of disease-causing miasmas, a concept too vague to be useful. The germ theory of infection had not yet led to any treatments for the large number of patients who had infections. There were no effective drugs. It took decades to find them, but two approaches emerged. 

The first, developed by Paul Ehrlich, came from chemistry. Ehrlich was a microbiologist, pathologist and chemist who noticed that some arsenic-containing compounds had antibacterial effects, but they were too toxic to inject into patients. He and his colleagues synthesized a large series of chemicals containing arsenic and asked whether they killed the bacteria that cause syphilis, Tryponema pallidum. In 1908, they found one, called Salvarsan 606, that could cure rabbits of syphilis.

It became the most widely prescribed drug in the world, despite opposition from religious authorities who thought that syphilis was punishment for sin and Erhlich should not interfere. That did not stop the afflicted from taking what came to be called Dr. Ehrlich’s Magic Bullet (See the 1940 film with Edward G. Robinson by the same name). The same approach, based on testing many variants of cloth dyes for antibacterial activity, led others to the first sulfa drug, Prontosil, in 1932. This approach still works and with advances in chemistry, informatics and robotics yields many useful drugs, but not, so far, new classes of antibiotics.

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The second approach is to let evolution do most of the work. Alexander Fleming at St. Mary’s Hospital Medical School in London noticed that some fungi compounds kill other microorganisms. Fleming cultured Staphylococcus aureus from patients in an effort to control these infections by injecting antibodies. One day he left some petri dishes with Staph aureus colonies growing on them and went on vacation; when he came back he found that a fungus had contaminated his petri dishes. Fortunately, he noticed that no bacterial colonies grew near the fungus and surmised that Penicillium notatum secreted something that killed Staph aureus. This secretion, called mold juice, also killed other harmful bacteria. He published in 1929, but he did not succeed in purifying the active substance. A shy man, he could not find a chemist to help him.

In Oxford, the chemists Howard Florey and Ernst Chain took up the purification of penicillin. As World War II approached, they succeeded in purifying small amounts of penicillin and made a start on its chemical structure. They could cure infections in mice, but because the fungus had to grow on a Jello-like surface, production was limited to a few patients. It was enough, however, to prove the concept. 

The story shifts to Peoria, Ill., where an effort was underway to find more productive strains of Penicillium. A young mycologist named Kenneth Raper realized that if a variant of the Penicillium mold could grow in a thousand-liter fermenter, production would be much more efficient. His technician found such a mold on a cantaloupe and, luckily, it secreted a lot of penicillin. They grew the new Penicillium isolate in fermenters using corn syrup to feed the mold. Illinois had (and has) lots of high-fructose corn syrup. We try to avoid consuming it now, but in the run-up to D-Day it was just the thing for penicillin production. The penicillin project was not as large as the wartime Manhattan or Radar projects, but it was critical. By D-Day, in June 1944, there was enough penicillin to treat all infected soldiers, saving many from infections.

The next 30 years were a golden age of discovery for new antibiotics, which were used to treat many of the infections that killed the residents of Norfolk, Conn., in 1872 to 1874, with which this series began. Tuberculosis was treatable with streptomycin and isoniazid as were many other infections. But Fleming had warned in 1940 that bacteria could find a means to destroy penicillin. That warning has now expanded into a threat that makes certain bacteria impervious to all antibiotics, the subject of the next column in this series.

Richard Kessin is professor emeritus of pathology and cell biology at Columbia University. He lives in Norfolk. The other columns in this series can be found at www.tricornernews.com/category/opinion-author/body-scientific.