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Antimicrobial Agents in the Treatment of Infectious Disease
(page 1)
(This chapter has 6 pages)
© 2009 Kenneth Todar, PhD
Introduction
Most microbiologists distinguish two groups of antimicrobial agents
used in the treatment of infectious disease: antibiotics, which
are natural substances produced by certain groups of microorganisms,
and chemotherapeutic agents, which are chemically synthesized.
A hybrid substance is a semisynthetic antibiotic, wherein a
molecular version produced by the microbe is subsequently modified by
the chemist to achieve desired properties. Furthermore, some
antimicrobial compounds, originally discovered as products of
microorganisms, can be synthesized entirely by chemical means. In the
medical and parmaceutical worlds, all these antimicrobial agents used
in the treatment of disease are referred to as antibiotics,
interpreting the word literally.
The modern era of antimicrobial chemotherapy began in 1929, with
Fleming's discovery of the powerful bactericidal substance, penicillin,
and Domagk's discovery in 1935 of synthetic chemicals (sulfonamides)
with broad antimicrobial activity.
In the early 1940's, spurred partially by the need for antibacterial
agents in WW II, penicillin was isolated and purified and injected into
experimental animals, where it was found not only to cure infections
but also to possess incredibly low toxicity for the animals. This fact
ushered into being the age of antibiotic chemotherapy, and an intense
search for similar antimicrobial agents of low toxicity to animals that
might prove useful in the treatment of infectious disease. The rapid
isolation of streptomycin, chloramphenicol and tetracycline soon
followed, and by the 1950's, these and several other antibiotics were
in clinical usage.
Microorganisms that Produce Antibiotics
The bacterial colonies at 10 o'clock, 2
o'clock and 8 o'clock on this agar plate are producing antibiotics that
inhibit encroachment by the mold which is growing out from the center.
Most of the natural antibiotics that are being used in agriculture and
medicine are produced by three unrelated groups of microbes, including
eucaryotic molds and two types of spore-forming bacteria. However, many
culturable, and some non culturable microbes, have been shown to
produce various substances that inhibit other organisms that grow in
their space. If we consider antibiotics as secondary metabolites of
microbes, it narrows the field to the handful of microbes discussed
below.
1. Penicillium and Cephalosporium molds
produce beta-lactam antibiotics such as penicillin and cephalosporin
and their relatives. They also produce the base molecule for
development of semisynthetic beta-lactam antibiotics, such as
amoxacillin and ampicillin. Beta-lactams are used to treat about
one-third of outpatients with bacterial infections.
The natural habitat of molds is soil. And although sex is sometimes
involved, they reproduce by spore formation. They are foremost in their
abilities to degrade organic matter, and they play their most important
role in natures in biodegradation and the carbon cycle. Most of us know
that molds will grow on nearly anything that is organic and moist, so
they are also responsible for a lot food spoilage as well as
decomposition of our structural materials and textiles. "Nothing is
forever", with molds around.
Three colonies of a Penicillium mold growing on an
agar medium. The green fuzzy appearance is the asexual spores of the
fungus.
2. Actinomycetes, mainly Streptomyces species, produce
tetracyclines, aminoglycosides (streptomycin and its relatives),
macrolides (erythromycin and its relatives), chloramphenicol,
ivermectin, rifamycins, and most other clinically-useful antibiotics
that are not beta-lactams. Actinomycetes are the
mainstay of the antibiotics industry.
Actinomycetes are a group of branched bacteria that reproduce by spore
formation. They come from a phylum of Bacteria, Actinobacteria, and they are landed
in Order Actinomycetales.
Some of the representative family include such diverse bacteria as Actinomyces, Corynebacterium, Nocardia,
Propionibacter, Streptomyces, Micromonospora and Frankia. Most actinomycetes are
inhabitants of the soil. The characteristic odor of damp soil is due to
the production of substances, called geosmins, by these bacteria
Two
different actinomycetes were spotted in the center of the agar plate
about two centimeters apart. This peculiar pattern of growth was
observed after a 10-day incubation period. What could be going on?
Courtesy of Jerry Ensign Department of Bacteriology. "Chance favors the
prepared mind."
3. Bacillus species, such as B. polymyxa and
B.
subtilis, produce polypeptide antibiotics (e.g. polymyxin and
bacitracin), and B. cereus produces zwittermicin. Bacillus species have the
relatively rare ability to form a type of resting cell called an
endospore. Bacilli are Gram-positive, rod-shaped, aerobic bacteria that
live in the soil. They play an important ecological role in aerobic
decomposition, biodegradation and mineral recycling.
A swirl of Bacillus mycoides colonies growth amidst other bacteria and
molds from the soil. The swirls are always counterclockwise, at least
in the Northern Hemisphere where I have seen it.
These organisms all have in common that they live in soil and
they form some sort of a spore or resting structure. It is not known
why these
microorganisms produce antibiotics, but the answer may be in the
obvious -
it affords them some nutritional or spatial advantage in their habitat
by
antagonizing the competition; or it may be in the subtle - it acts as
some sort of hormone or signal molecule associated with sporulation or
dormancy or germination. Antibiotics are secondary metabolites and they
are produced at the same
time that the cells begin their sporulation processes.
Antibiotics tend to be rather large, complicated organic molecules and
may require as many as 30 separate enzymatic steps to synthesize. The
maintenance of a substantial component of the bacterial genome devoted
solely to the
synthesis of an antibiotic leads one to conclude that the antibiotic
is
important, if not essential, to the survival of these organisms in
their
natural habitat.
Most of the microorganisms that produce antibiotics are resistant to
the action of their own antibiotic, although the organisms are affected
by other antibiotics, and their antibiotic may be effective against
closely-related strains. In most cases, how or why bacteria are
resistant to their own antibiotics is also unknown, but it may be worth
pondering or studying if we are to
understand the cellular and molecular basis of drug resistance in
pathogens.
chapter continued
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