• Doug Neckers

Penicillin

Updated: Apr 29

Penicillin was discovered by accident, or better by a prepared mind able to discern when something accidentally happened that might be useful. Alexander Fleming worked in St. Mary’s Hospital labs in London, was a bacteriologist and, as such, following the strains of bacteria showing up in that Hospital. Influenza was a huge issue in all hospitals in the 1920’s so much of Fleming’s work was targeted at treating, and curing, ‘the flu’. Chemotherapy - treating illness with chemicals - began when Paul Ehrlich used an arsenic compound to treat final stage syphilis. So hopeful physicians were looking for magic, chemical bullets. And Fleming found the most successful one ever, penicillin. When he sneezed into a culture of staphylococcus bacteria, and the area in the culture into which particles from his sneeze went, showed a clearing of the bacteria, he noticed it. Penicillin, the fungus, had been introduced inadvertently to Petri dishes of growing staphylococcus bacteria in Fleming’s lab where dishes of brewing bugs were all over. Where the penicillin was, the bacteria died. That’s how the ‘antibiotic’ action of penicillin was discovered. Some years later, Howard Florey at Oxford picked up the work, and eventually began using what little penicillin he could grow to treat bacterial infections.

Florey and collaborator Abraham Chain, a refugee from the Nazis on the continent, identified the exact penicillium, grew it in Petri dishes and bedpans, and harvested it in small quantities testing those first on mice and soon on patients suffering from bacterial infections that were at a clinic in Oxford. A man with an both staphococcus and streptococcus infections caused from trimming a rose was treated and started to recover. But penicillin wasn’t sufficiently available for an adult, and the drug - though successful - wasn’t enough. When that patient died, future testing was restricted to children. By the end of the year, the ‘wonder drug from a blue green mold’ had reached the popular press, and was reported in Time 1941, 38 55-6 with the caution that it was in far too short supply to be useful until it could be made synthetically.

With London under siege as the Battle of Britain took full force, Florey recognized he needed help, that penicillin was worth it, and, with Norman Heatley, a bacteriologist, brought the fungus to the US to get that help in June, 1941. Studies were already ongoing here based on strains developed at Columbia and the Mayo Clinic. Florey and Heatley were directed to the Department of Agriculture’s labs in Peoria, IL. This lab was set up during the depression to find uses for the side products arising from the processing of corn. American scientists were trying to find new uses for corn product wastes. In order to extract ‘corn starch’ from kernels of corn, the corn was ‘steeped, i. e. heated under pressure in water. The starch - blanched kernels were removed, and the liquor in which the corn had been steeped left behind. One of the uses of corn steep liquor being examined was directed by Rober. D. Coghill an alumnus of the University of Kansas (as am I - go Jayhawks) who had followed in other KU scientist’s footsteps and gone to Yale for his advanced degrees. While at Yale, among other things, Coghill met, and advised, an undergraduate majoring in chemistry, Paul Block, Jr. There were strong initiatives in the Yale chemistry of the time to study vitamins and hormones. Coghill, to whom Block dedicated his Ph. D. thesis earned at Columbia in 1943, advised Block to study the thyroid and the thyroid hormone, thyroxin. Dr. Block made it his life’s passion. The discovery of corn steep liquor as an ingredient in the broth where penicillin could be grown in quantity was the most important advance in the development of the drug. For all of its early history, commercial penicillin was prepared in fermentation tanks. Its synthesis, when it happened in 1957, was complex requiring specific tricks. One of the reason penicillin is so effective in lysing (breaking up) bacteria, is because it is relatively reactive organic compound that can attack bacterial cell walls. But problems remained. By this time, the US government had decided penicillin was a weapon of war. The government leadership, in addition to causing untold levels of secrecy, worried about production. Soon industries were being invited to participate in the commercialization and that raised international intellectual property issues. The laboratories at Merck in Rahway, NJ were ahead of the rest. They had hired a bright young chemist from the University of Michigan, John T. Sheehan, where he worked under Max Tishler (known for the first synthesis of cortisone) on the penicillin problem. Penicillin, when isolated and purified from natural sources was said to be a ‘rather simple small organic molecule, that should easily lend itself to synthetic preparation’.


But for those around the world fighting in WWII, penicillin is the reason many of them remained after the War to tell the story. It was literally the first wonder drug. Millions were and are being saved because penicillin exists. I first got interested in its chemistry because I knew Paul Block, and after his death, wanted to read his Ph.D. dissertation. When I did so, I discovered Robert D. Coghill; and when I did I discovered Coghill’s connection to penicillin, Yale chemistry and the University of Kansas in that order. I also became fascinated by Sheehan’s history - his post-doctoral work became the commercial preparation of RDX, the world’s most vicious nitrogen explosive; and he, in 1957, completed the penicillin synthesis Pencillin is arguably the small molecule drug that saved more lives than any in history.

There are many important side stories to the penicillin story. First, why did the German chemical industry not pursue it. The answer was and is that they looked at Fleming’s work, and Florey’s, but decided after preliminary tests that they had a corner on sulfanilamide so why bother with another antibiotic. In many ways the discovery and development of ‘sulfa’ is as interesting as was the development of penicillin. Essentially there was no research on penicillin in German companies until well after the War. The Japanese, on the other hand, had developed a medium from rice hulls that could be used as a nutrient to grow penicillin well, too. Commercial production was started there, but the deviating end of the War truncated it.


Before 2020, I have said that the development of antibiotics to kill bacteria, and various vaccines, in particular the polio vaccine, were mankind’s greatest advances over the miscreants of nature. Public health was just being addressed. The vaunted Yale chemistry department’s first group of Ph. D. students were working locally putting in place sewers for New Haven where the University was located. Sewers in my mother’s hometown, Holland, Michigan went a few blocks deep from the outlet to Lake Michigan when she lived at home; but it took until the 1930’s for the sewers to reach most of the community. And where they did go, the city grew too. And then, as now, sewers were sources of information. In the 1940’s Rene Dubos at Rockefeller University mined the sewers for a microbe that would break down the polysaccharide capsule of a deadly strain of bacteria causing pneumonia. He was responsible for the antibiotics such as the occasionally still used gramicidin.


After 2020, and the introduction of m(RNA) vaccines for viruses, this acclimation could be added too. It is still too early to tell if the m(RNA) vaccines will do for solving viral diseases, what penicillin did to conquer bacterial diseases. For that answer, we’ll just have to wait.

Photo by National Cancer Institute on Unsplash


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With Dr. Doug Neckers

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