By Barry C. Fox, M.D., University of Wisconsin
Almost everyone has heard of the urban legend of the discovery of penicillin by Dr. Alexander Fleming. But one might be surprised to know that several efforts toward the development of antibiotics preceded Fleming’s discovery by at least several decades.
Striving for a Magic Bullet
Scientists at the time were striving for a ‘magic bullet’ that could rid the body of infecting organisms without harming the patient, a concept still striven for today. One such effort occurred in 1888 when German scientists observed that the bacterium Pseudomonas Aeruginosa produced a substance in the test tube known as pyocyanase.
Laboratory studies showed that pyocyanase killed dangerous bacteria like staphylococcus. However, when it was tried in patients, it was unsuccessful and even toxic. Nevertheless, pyocyanase was used for nearly 30 more years as a topical skin antibiotic.
In 1910, Paul Ehrlich, a German chemist, took a different approach. He used a chemical compound called salvarsan, an arsenic derivative, to treat syphilis. The drug was toxic, but it represented the first partial success in syphilis treatment.
Dr. Fleming was working in London in the 1920s on a natural chemical from human tears that had antibacterial properties, called lysozyme, which caused bacteria to fall apart. This too never really succeeded as an antibiotic, but it did show that humans could produce a natural antibacterial substance.
This is a transcript from the video series An Introduction to Infectious Diseases. Watch it now, on Wondrium.
The Fate of the World in a Petri Dish
In 1928, a strange twist of fate occurred—after returning from vacation, Fleming noticed a petri dish with staphylococcal bacteria whose growth had been inhibited by a mold growing in the adjacent area.
He eventually demonstrated that the mold was a Penicillium fungus. So, an unknown substance, produced by the mold, must have traveled across the agar plate to kill the bacteria. This substance was henceforth named penicillin. The original dried plate still remains today in the archives of St. Mary’s Hospital in London. But it would still be another 10 to 15 years before full advantage could be taken of this discovery, with penicillin’s first human use in 1941.
Although Dr. Fleming warned in 1945 that the misuse of penicillin would lead to mutant-resistant bacteria, by 1946, a study showed that 14 percent of staph aureus were already resistant to penicillin, and today it’s greater than 95 percent.
In the 1930s, Gerhard Domagk, a German professor, was examining an assortment of chemical dyes for their possible antibiotic effect. One man-made dye, called prontosil, was active against mice infected with streptococcal bacteria.
Sulfa even saved the life of Winston Churchill in 1943, when he developed pneumonia while traveling in North Africa. Churchill said: “There is no doubt that pneumonia is a very different illness from what it was before this marvelous drug was discovered.”
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Buckle Up because It Is Full Speed Ahead
In 1939, scientists working at the Rockefeller Institute discovered a bacterium in the soil, Bacillus Brevis, which produced a compound that inhibited gram-positive bacteria. This substance contained gramicidin, which has antibacterial properties. But unfortunately, gramicidin was also too toxic when orally consumed.
But similar to Fleming’s pyocyanase, gramicidin was used as a topical skin antibiotic. Elsie, the famous cow of the Borden Company, was one of the first patients to be successfully treated with gramicidin. While attending the 1939 World’s Fair, Elsie developed mastitis, an infection of her udder tissues.
In the 1940s fueled by the new excitement that was generated from sulfonamide and gramicidin, there was renewed interest in pursuing the development of penicillin. Englishman Howard Florey and German-born Ernst Chain learned how to extract penicillin and to produce it in sufficient amounts to test in animals.
Penicillin was subsequently released for human testing for those who were considered near death, often with dramatically favorable results. Florey also managed to convince the United States government to support large-scale production.
The Discovery of Streptomycin
The story of antibiotics would not be complete unless it included the discovery of streptomycin in 1943, the first useful drug for tuberculosis, or TB treatment. The bacterium that produces streptomycin was found in a farmer’s field. Not only was streptomycin able to treat TB, but it was useful to cure gram-negative bacterial infections, which penicillin could not.
However, when streptomycin was used alone for TB, not unexpectedly, resistance emerged, and damage by streptomycin to the kidneys prompted further development of an improved antibiotic, neomycin.
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The Antibiotics That Attacked Everything
Up to that point, the antibiotics discovered attacked either gram-positive or gram-negative bacteria, but not both. In 1947, a Yale researcher discovered an antibiotic from a soil sample collected in a field in Caracas, Venezuela, and he named it chloramphenicol. This was the first ‘broad-spectrum’ antibiotic to exhibit activity against germs with different cell walls and varied gram staining characteristics.
For someone who was a child in the 1950s, it is likely that they were treated with this antibiotic. However, chloramphenicol isn’t heard about today. It was a first-line drug for typhus and typhoid fever in the mid-1900s. Unfortunately, a rare idiosyncratic side effect of total blood-cell production shutdown occurred in a tiny percentage of treated patients, but this was enough to taint the use of chloramphenicol.
In 1948, another broad-spectrum antibiotic named aureomycin was being studied. This was a prototype drug for the class of drugs known as tetracycline.
In 1964, other beta lactam drugs known as cephalosporins made their debut. They are structurally similar to penicillin and disrupt the bacterial cell wall in a very similar manner. They were discovered from extracts of a mold found in a sewer off the coast of Sardinia by an Italian microbiologist. It took nearly two decades, however, to purify these antibiotics for clinical use.
Cephalexin, an oral antibiotic, made its debut in 1967 and is still one of the major first-line antibiotics in use today. The intravenous form of cefazolin is given to virtually every patient receiving antibiotic prophylaxis for surgical procedures today.
Common Questions about a Brief History of Antibiotics
Yes. Even Dr. Fleming himself expected the misuse of Penicillin in 1945, predicting that it would lead to more resistant bacteria.
A broad-spectrum antibiotic can have effects against different types of bacteria. Unlike Penicillin, this type of antibiotic wasn’t used before 1947 until a researcher found one type of it in a soil sample.
There is a natural chemical in human tears that acts as sort of a natural antibiotic. Dr. Fleming was studying this substance before he discovered Penicillin.
