Antibacterial drugs

Mechanisms of genetic resistance to antimicrobial agents:

Bacteria have developed, or will develop, genetic resistance to all known antimicrobial agents that are now in the marketplace. The five main mechanisms that bacteria use to resist antibacterial drugs are shown in the figure.
a | The site of action (enzyme, ribosome or cell-wall precursor) can be altered. For example, acquiring a plasmid or transposon that codes for a resistant dihydrofolate reductase confers trimethoprim resistance to bacteria52.
b | The inhibited steps can be by-passed.
c | Bacteria can reduce the intracellular concentration of the antimicrobial agent, either by reducing membrane permeability, for example, as shown by Pseudomonas aeruginosa53, or by active efflux of the agent54.
d | They can inactivate the drug. For example, some bacteria produce beta-lactamase, which destroys the penicillin beta-lactam ring50, 51 .
e | The target enzyme can be overproduced by the bacteria.



The invention:

Sulfonamides and other drugs that have proved effective
in combating many previously untreatable bacterial diseases.

The people behind the invention:

Gerhard Domagk (1895-1964), a German physician who was
awarded the 1939 Nobel Prize in Physiology or Medicine
Paul Ehrlich (1854-1915), a German chemist and bacteriologist
who was the cowinner of the 1908 Nobel Prize in Physiology
or Medicine.

The Search for Magic Bullets

Although quinine had been used to treat malaria long before the
twentieth century, Paul Ehrlich, who discovered a large number of
useful drugs, is usually considered the father of modern chemotherapy.
Ehrlich was familiar with the technique of using dyes to stain
microorganisms in order to make them visible under a microscope,
and he suspected that some of these dyes might be used to poison
the microorganisms responsible for certain diseases without hurting
the patient. Ehrlich thus began to search for dyes that could act
as “magic bullets” that would destroy microorganisms and cure
diseases. From 1906 to 1910, Ehrlich tested numerous compounds
that had been developed by the German dye industry. He eventually
found that a number of complex trypan dyes would inhibit the
protozoans that caused African sleeping sickness.
Ehrlich and his coworkers also synthesized hundreds of organic
compounds that contained arsenic. In 1910, he found that one of
these compounds, salvarsan, was useful in curing syphilis, a sexually
transmitted disease caused by the bacterium Treponema. This
was an important discovery, because syphilis killed thousands of
people each year. Salvarsan, however, was often toxic to patients,
because it had to be taken in large doses for as long as two years to
effect a cure. Ehrlich thus searched for and found a less toxic arsenic
compound, neosalvarsan, which replaced salvarsan in 1912.

In 1915, tartar emetic (a compound containing the metal antimony)
was found to be useful in treating kala-azar, which was
caused by a protozoan. Kala-azar affected millions of people in Africa,
India, and Asia, causing much suffering and many deaths each
year. Two years later, it was discovered that injection of tartar emetic
into the blood of persons suffering from bilharziasis killed the
flatworms infecting the bladder, liver, and spleen. In 1920, suramin,
a colorless compound developed from trypan red, was introduced
to treat African sleeping sickness. It was much less toxic to the patient
than any of the drugs Ehrlich had developed, and a single dose
would give protection for more than a month. From the dye methylene
blue, chemists made mepacrine, a drug that was effective
against the protozoans that cause malaria. This chemical was introduced
in 1933 and used duringWorldWar II; its principal drawback
was that it could cause a patient’s skin to become yellow.

Well Worth the Effort

Gerhard Domagk had been trained in medicine, but he turned to
research in an attempt to discover chemicals that would inhibit or
kill microorganisms. In 1927, he became director of experimental
pathology and bacteriology at the Elberfeld laboratories of the German
chemical firm I. G. Farbenindustrie. Ehrlich’s discovery that
trypan dyes selectively poisoned microorganisms suggested to Domagk
that he look for antimicrobials in a new group of chemicals
known as azo dyes. A number of these dyes were synthesized
from sulfonamides and purified by Fritz Mietzsch and Josef Klarer.
Domagk found that many of these dyes protected mice infected
with the bacteria Streptococcus pyogenes. In 1932, he discovered that
one of these dyes was much more effective than any tested previously.
This red azo dye containing a sulfonamide was named prontosil
rubrum.
From 1932 to 1935, Domagk began a rigorous testing program to
determine the effectiveness and dangers of prontosil use at different
doses in animals. Since all chemicals injected into animals or humans
are potentially dangerous, Domagk determined the doses that
harmed or killed. In addition, he worked out the lowest doses that
would eliminate the pathogen. The firm supplied samples of the drug to physicians to carry out clinical trials on humans. (Animal
experimentation can give only an indication of which chemicals
might be useful in humans and which doses are required.)
Domagk thus learned which doses were effective and safe. This
knowledge saved his daughter’s life. One day while knitting, Domagk’s
daughter punctured her finger with a needle and was infected
with a virulent bacteria, which quickly multiplied and spread
from the wound into neighboring tissues. In an attempt to alleviate
the swelling, the infected area was lanced and allowed to drain, but
this did not stop the infection from spreading. The child became
critically ill with developing septicemia, or blood poisoning.
In those days, more than 75 percent of those who acquired blood
infections died. Domagk realized that the chances for his daughter’s
survival were poor. In desperation, he obtained some of the powdered
prontosil that had worked so well on infected animals. He extrapolated
from his animal experiments how much to give his
daughter so that the bacteria would be killed but his daughter
would not be poisoned. Within hours of the first treatment, her fever
dropped, and she recovered completely after repeated doses of
prontosil.

Impact

Directly and indirectly, Ehrlich’s and Domagk’s work served to
usher in a new medical age. Prior to the discovery that prontosil
could be use to treat bacterial infection and the subsequent development
of a series of sulfonamides, or “sulfa drugs,” there was no
chemical defense against this type of disease; as a result, illnesses
such as streptococcal infection, gonorrhea, and pneumonia held terrors
of which they have largely been shorn.Asmall injury could easily
lead to death.
By following the clues presented by the synthetic sulfa drugs and
how they worked to destroy bacteria, other scientists were able to
develop an even more powerful type of drug, the antibiotic. When
the American bacteriologist Rene Dubos discovered that natural organisms
could also be used to fight bacteria, interest was renewed in
an earlier discovery by the Scottish bacteriologist Sir Alexander: the
development of penicillin.
Antibiotics such as penicillin and streptomycin have become
some of the most important tools in fighting disease. Antibiotics
have replaced sulfa drugs for most uses, in part because they cause
fewer side effects, but sulfa drugs are still used for a handful of purposes.
Together, sulfonamides and antibiotics have offered the possibility
of a cure to millions of people who previously would have
had little chance of survival.