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.
Table taken from The Antibiotic Paradox by Stuart Levy
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.
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.
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
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.
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.
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
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.
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”
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.
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.
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
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.
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
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.
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
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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 Milton Wainwright, “Miracle Cure: The Story of Penicillin and the Golden Age of Antibiotics.” (Oxford: Basil Blackwell, 1990).
 Stuart B. Levy, “The Antibiotic Paradox.” (New York: Plenum Press, 1992), 4.
 Levy, 7.
 Levy, 10.
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