History of the development of antibiotics WORLD OF MICROBIOLOGY AND IMMUNOLOGY276•
See alsoAIDS; Bacteria and bacterial infection; Epidemics
and pandemics; Infection control; Public health, current issuesHISTORY OF THE DEVELOPMENT OF
ANTIBIOTICSHistory of the development of antibioticsThe great modern advances in chemotherapyhave come from
the chance discovery that many microorganismssynthesize
and excrete compounds that are selectively toxic to other
microorganisms. These compounds are called antibioticsand
have revolutionized medicine. The period since World War II
has seen the establishment and extremely rapid growth of a
major industry, using microorganisms for the synthesis of,
amongst other compounds, chemotherapeutic agents. The
development of this industry has had a dramatic and far-reach-
ing impact. Nearly all bacterial infectious diseases that were,
prior to the antibiotic era, major causes of human death have
been brought under control by the use of chemotherapeutic
drugs, including antibiotics. In the United States, bacterial
infection is now a less frequent cause of death than suicide or
traffic accidents.
The first chemotherapeutically effective antibiotic was
discovered in 1929 by Alexander Fleming(1881–1955), a
British bacteriologist, who had long been interested in the
treatment of wound infections. On returning from a vacation
in the countryside, he noticed among a pile of petri dishes on
his bench one that had been streaked with a cultureof
Saphyloccocus aureuswhich was also contaminated by a sin-
gle colonyof mold. As Fleming observed the plate, he noted
that the colonies immediately surrounding the mold were
transparent and appeared to by undergoing lysis. He reasoned
that the mould was excreting into the medium a chemical that
caused the surrounding colonies to lyse. Sensing the possible
chemotherapeutic significance of his observation, Fleming
isolated the mold, which proved to be a species of Penicillium,
and established that culture filtrates contained an antibacterial
substance, which he called penicillin.
Although it has often been suggested that many bacteri-
ologists must have observed petri dishes that were similarly
contaminated and therefore similar in appearance to Fleming’s
dish, such speculation is undoubtedly false. As subsequent
experiments have shown, a highly unusual series of events
must have occurred in order to produce the results seen on
Fleming’s plate: contaminationmust have occurred at the time
the plate was streaked with bacteria(prior growth of either
would have prevented growth of the other in the immediate
vicinity); the inoculated petri dish must not have been incu-
bated (if it had been the bacterium would have outgrown the
mold); the room temperature of the laboratory must have been
below 68°F [20° C] (a temperature that probably did occur
during a brief cold storm in London in the summer of 1928).
Penicillin proved to be chemically unstable and Fleming
was unable to purify it. Working with impure preparations, he
demonstrated its remarkable effectiveness in inhibiting the
growth of many Gram-positive bacteria, and he even used it
with success for the local treatment of human eye infections.In the meantime, the chemotherapeutic effectiveness of other,
non-antibiotic compounds such as sulfonamides had been dis-
covered, and Fleming, discouraged by the difficulties in puri-
fying penicillin, abandoned further work on the problem.
Ten years later a group of British scientists headed by
H.W. Florey(1898–1968) and E. Chain(1906–1979) resumed
the study of penicillin. Clinical trials with partly purified
material were dramatically successful. By this time, however,
Britain was at war; and the industrial development of peni-
cillin was undertaken in the United States, where an intensive
program of research and development was begun in many lab-
oratories. Within three years, penicillin was being produced on
an industrial scale. Today it remains one of the most effective
chemotherapeutic agents for the treatment of many bacterial
infections.
Rather than being a single substance, penicillin turned
out to be a class of compounds. The various penicillins vary
with respect to the chemical composition of their side chain.
The penicillin that was first isolated in Peoria, Illinois, desig-
nated penicillin G, carried a benzyl side chain. The penicillin
isolated soon after in England, designated penicillin F, carried
an isopentanyl side chain. By varying the composition of the
fungal growth media, a variety of penicillins collectively
termed biosynthetic penicillins, have been synthesized.
Penicillin G proved the most successful and later it became
possible to remove the side chain and replace it by a variety of
chemical substituents, thereby producing semisynthetic peni-
cillins. For example, penicillin V is resistant to acid and there-
fore can be administered orally because it is not inactivated in
the stomach; ampicillin is also acid resistant and also effective
against enteric bacteria; oxacillin is resistant to the action of
-lactamase, the enzyme produced by certain “penicillin-
resistant” strains of bacteria.
The remarkable chemotherapeutic efficacy of penicillin
for certain bacterial infections, primarily those caused by
Gram-positive bacteria, prompted intensive research into new
antibiotics. In the 1940s, a second clinically important antibi-
otic, streptomycin, effective against both Gram-negative bac-
teria and Mycobacterium tuberculosis,was discovered by A.
Schatz and S. Waksman. This was the first example of a broad-
spectrum antibiotic. Other antibiotics with even broader spec-
tra of activity, such as the tetracyclines, were subsequently
discovered. The search for new antibiotics remains an empiri-
cal enterprise. So far, they have proved very effective as anti-
bacterial agents, although some bacteria do acquire resistance
to antibiotics, so there is a continuous search for new and
effective antibacterial agents. Antibiotics have proved less
effective in the treatment of fungal infections. Antifungal
antibiotics, such as nystatin and amphoterecin B are consider-
ably less successful therapeutically than their bacterial coun-
terparts, at least in part because their toxicity is far less
selective. There are no known antiviral antibiotics.
Since 1945, thousands of different antibiotics produced
by fungi, actinomycetes or unicellular bacteria have been iso-
lated and characterized. A small fraction of these are of thera-
peutic value. Their nomenclature is complicated as one
antibiotic may be sold under several different names. For
example in the United States the compound, which in Europewomi_H 5/6/03 3:21 PM Page 276