History of Antibiotics
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Introduction

The search for antibiotics began in the late 1800s, with the growing acceptance of the germ theory of disease, a theory which linked bacteria and other microbes to the causation of a variety of ailments.  As a result, scientists began to devote time to searching for drugs that would kill these disease-causing bacteria.  The goal of such research was to find so-called “magic bullets” that would destroy microbes without toxicity to the person taking the drug.[1]

Table taken from The Antibiotic Paradox by Stuart Levy

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Early Antibacterial Agents 

One of the earliest areas of scientific exploration in this field was whether harmless bacteria could treat diseases caused by pathogenic strains of bacteria.  By the late 19th century there were a few notable breakthroughs.  In 1877, Louis Pasteur showed that the bacterial disease anthrax, which can cause respiratory failure, could be rendered harmless in animals with the injection of soil bacteria.  In 1887, Rudolf Emmerich showed that the intestinal infection cholera was prevented in animals that had been previously infected with the streptococcus bacterium and then injected with the cholera bacillus.

While these scientists showed that bacteria could treat disease, it was not until a year later, in 1888, that the German scientist E. de Freudenreich isolated an actual product from a bacterium that had antibacterial properties.  Freudenreich found that the blue pigment released in culture by the bacterium Bacillus pyocyaneus arrested the growth of other bacteria in the cell culture.  Experimental results showed that pyocyanase, the product isolated from B. pyocyaneus, could kill a multitude of disease-causing bacteria.  Clinically, though, pyocyanase proved toxic and unstable, and the first natural antibiotic discovered could not be developed into an effective drug.

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Alexander Fleming and the Discovery of Penicillin

In the early 1920s, the British scientist Alexander Fleming reported that a product in human tears could lyse bacterial cells.  Fleming’s finding, which he called lysozyme, was the first example of an antibacterial agent found in humans.  Like pyocyanase, lysozyme would also prove to be a dead end in the search for an efficacious antibiotic, since it typically destroyed nonpathogenic bacterial cells.

Fleming’s second discovery, though, would change the course of medicine.  In 1928, Fleming serendipitously discovered another antibacterial agent.  Returning from a weekend vacation, Fleming looked through a set of old plates that he had left out.  On one such plate, he found that colonies of Staphylococcus, which he had streaked out, had lysed.  Fleming observed that bacterial cell lysis occurred in an area adjacent to a contaminant mold growing on the plate and hypothesized that a product of the mold had caused the cell lysis.

While Fleming generally receives credit for discovering penicillin, in fact technically Fleming rediscovered the substance.  In 1896, the French medical student Ernest Duchesne originally discovered the antibiotic properties of Penicillium, but failed to report a connection between the fungus and a substance that had antibacterial properties, and Penicillium was forgotten in the scientific community until Fleming’s rediscovery.

Through follow-up work, Fleming showed experimentally that the mold produced a small substance that diffused through the agar of the plate to lyse the bacteria.  He named this substance penicillin after the Penicillium mold that had produced it.  By extracting the substance from plates, Fleming was then able to directly show its effects.  Important to its discovery was the penicillin had destroyed a common bacterium, Staphylococcus aureus, associated with sometimes deadly skin infections.

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The Development of Penicillin as a Common Antibacterial Agent

While Fleming had made the initial discovery, he was unable to carry his research significantly further.  Because he was unable to purify significant quantities of penicillin, Fleming was not able to conduct clinical trials on animals and humans to test the agent’s efficacy, and last published any work on penicillin around 1931.

It was not until about ten years after penicillin’s rediscovery, in 1939, that Howard Florey, Ernst Chain, and Norman Heatley picked up the project.  The trio obtained the Penicillium fungus from Fleming and were able to overcome the technical difficulties that had plagued him, in the process spectacularly showing penicillin’s efficacy in the clinical setting.  Animals and humans that were near-death with bacterial infections were miraculously cured with even small amounts of the drug in its crude form.

Cross-continent cooperation in the early 1940s resulted in the increased scale of penicillin production.  Because England lacked the capabilities to mass produce the drug, since the country had devoted almost all of its industrial capacity to the war effort, the British worked together with the United States to make penicillin a reality.  The project has been called one of the great ventures of group research and collaboration. 

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The Public Becomes Aware of Penicillin

Given the political climate under which it was rediscovered and produced, it is not surprising that initially penicillin was used almost exclusively to treat soldiers injured during the war.  That would change, though, with one fateful disaster.

Perhaps penicillin’s most important clinical trial occurred after a fire at a Boston club, which resulted in numerous burn victims being sent to Boston-area hospitals.  At that time, it was common for severe burn victims to die of bacterial infections, such as those from Staphylococcus.  In response to this crisis, Merck rushed a large supply of a “priceless”[2] drug (penicillin) to the Massachusetts General Hospital.  The success that physicians had in treating severely burned victims that night was largely attributed to the effects of penicillin.  The fire—and the success of penicillin—made national headlines, vaulting the drug into the public spotlight.

By 1946, the drug had become widespread for clinical use.

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Early Warnings of Antibiotic Resistance

As early as 1945, in an interview with The New York Times, Fleming warned that the misuse of penicillin could lead to selection of resistant forms of bacteria.[3]  In fact, Fleming had already experimentally derived such strains by varying the dosage and conditions upon which he added the antibiotic to bacterial cultures.  As a result, Fleming warned that the drug carried a large potential for misuse, especially with patients taking it orally at home, and that inadequate treatments would likely lead to mutant forms.  Fleming posited that resistance to penicillin could be conferred in two ways – either through the strengthening of the bacterial cell wall which the drug destroyed, or through the selection of bacteria expressing mutant proteins capable of degrading penicillin.

Penicillin was available orally to the public without prescription until the mid 1950s.  During this period, the drug was indeed sometimes used inappropriately.  There are several accounts of patients, believing that penicillin was a miracle cure-all, using the drug for non-bacterial diseases, and also taking less than the optimal dose.

By 1946, one hospital reported that 14% of the strains of staph isolated from sick patients were penicillin resistant.  By the end of the decade, the same hospital reported that resistance had been conferred to 59% of the strains of staph studied.[4]

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Science Adapts and the Threat of Antibiotic Resistance Returns

The success of penicillin led scientists to intensify searches for new antibiotics that could treat other bacterial diseases, including those caused by now penicillin resistant strains.  One way that scientists combated  resistance was to chemically modify penicillin, creating derivatives of the chemical—such as ampicillin—that avoided enzymatic degradation.  Today, numerous penicillin derivatives exist.

It was not until the 1970s that antibiotic resistance was considered to be a real threat.  During the decade, there were two notable cases of resistant bacterial strains lethally infecting patients, in which a strain of bacteria that causes meningitis and ear infections in children and a strain that causes gonorrhea proved fatal.  Both strains had previously been able to be treated with penicillin or penicillin derivatives, and events like these marked the end of 30 years of successful treatment for these infections.

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Other Early Antibiotics

During the period between Fleming’s rediscovery and Florey and coworkers’ advancement of penicillin, a few other notable findings in the search for antibiotics were made.  In 1932, the German Gerhard Domagk turned his attention away from natural antibiotics and towards synthetic ones.  Domagk, who investigated the effects of different chemical dyes for their effects on bacterial infections, found that the dye Prontosil cured diseases caused by the streptococcus bacteria when injected into infected animals.  Later work showed that the active group of Prontosil was not the dye part of the molecule, but the sulfonamide group attached to it.  Both Prontosil and other sulfonamide derivatives proved highly successful, both in efficacy and lack of toxicity.  For this reason, this discovery has been credited for creating an atmosphere conducive to the development and production of penicillin.

Around the time that Florey and coworkers picked up the work on penicillin, the antibiotic gramicidin was isolated from a soil-inhabiting microbe.  Gramicidin, the first natural antibiotic extracted from soil bacteria, was able to arrest the growth of staphylococcus, but proved highly toxic.

In 1943, Selman Waksman and his group isolated another antibacterial agent from a soil bacterium, Streptomyces griseus.  Waksman’s antibiotic, streptomycin, proved effective against several common infections.  Most noteworthy was its ability to kill the bacterium Mycobacterium tuberculosis, the microbe causing tuberculosis, which had to that point resisted numerous methods of treatment.  Streptomycin, though, carried with it highly toxic side effects and a fast rate of mutation, making it not a viable clinical option.

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Penicillin: Structure and Function

Penicillin prevents cell wall synthesis, so that replicating bacteria will be unable to produce viable cells when they divide.  Penicillin acts by blocking the activity of the enzyme transpeptidase, which cross connects long polymers of sugars that form the bacterial cell wall.  The beta lactam ring on penicillin (see structure) irreversibly blocks the activity of the enzyme by covalently bonding with the functional end of the enzyme.  As a result, newly-formed cell walls will be structurally weak in some areas, causing water to rush in and rupture the cell.  

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Footnotes

[1] Milton Wainwright, “Miracle Cure: The Story of Penicillin and the Golden Age of Antibiotics.” (Oxford: Basil Blackwell, 1990).

[2] Stuart B. Levy, “The Antibiotic Paradox.” (New York: Plenum Press, 1992), 4.

[3] Levy, 7.

[4] Levy, 10.

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