Antimicrobial Agents in the Treatment of Infectious Disease
(This chapter has 6 pages)
© Kenneth Todar, PhD
Many therapeutically useful antibiotics owe their action to
inhibition of some step in the complex process of protein synthesis.
Their attack is always at one of the events occurring on the ribosome
and never at the stage of amino acid activation or attachment to a
particular tRNA. Most have an affinity or specificity for 70S (as
opposed to 80S) ribosomes, and they
achieve their selective toxicity in this manner. The most important
with this mode of action are the tetracyclines, chloramphenicol,
the macrolides (e.g. erythromycin) and the aminoglycosides
The aminoglycosides are products of Streptomyces
species and are represented by streptomycin, kanamycin,
tobramycin and gentamicin. These antibiotics exert their
activity by binding to bacterial ribosomes and preventing the
initiation of protein synthesis.
Streptomycin binds to 30S subunit of the bacterial ribosome,
specifically to the S12 protein which is involved in the initiation of
protein synthesis. Experimentally, streptomycin has been shown to
prevent the initiation of protein synthesis by blocking the binding of
initiator N-formylmethionine tRNA to the ribosome. It also prevents the
normal dissociation of ribosomes into their subunits, leaving them
mainly in their 70S form and preventing the formation of polysomes. The
overall effect of streptomycin seems to
be one of distorting the ribosome so that it no longer can carry out
normal functions. This evidently accounts for its antibacterial
but does not explain its bactericidal effects, which distinguishes
and other aminoglycosides from most other protein synthesis inhibitors.
is the first aminoglycoside antibiotic to be discovered, and was the
first antibiotic to be used in treatment of tuberculosis. It was discovered
in 1943, in
the laboratory of Selman Waksman at Rutgers University. Waksman
and his laboratory discovered several antibiotics, including
actinomycin, streptomycin, and neomycin.
Streptomycin is derived from
the bacterium, Streptomyces griseus. Streptomycin stops
bacterial growth by
inhibiting protein synthesis. Specifically, it binds to the 16S
rRNA of the bacterial ribosome, interfering with the binding of
formyl-methionyl-tRNA to the 30S subunit. This prevents initiation of
Kanamycin and tobramycin have been reported to bind
to the ribosomal 30S subunit and to prevent it from joining to the 50S
during protein synthesis. They may have a bactericidal effect because
leads to cytoplasmic accumulation of dissociated 30S subunits, which is
apparently lethal to the cells.
Aminoglycosides have been used against a wide variety of bacterial
infections caused by Gram-positive and Gram-negative bacteria.
Streptomycin has been used extensively as a primary drug in the
treatment of tuberculosis. Gentamicin is active against many
strains of Gram-positive and
Gram-negative bacteria, including some strains of Pseudomonas
aeruginosa. Kanamycin is active at low concentrations
against many Gram-positive
bacteria, including penicillin-resistant staphylococci. Gentamicin
and Tobramycin are mainstays for treatment of Pseudomonas infections.
An unfortunate side effect
of aminoglycosides has tended to restrict their usage: prolonged use is
known to impair kidney function and cause damage to the auditory nerves
leading to deafness.
Gentamicin is an aminoglycoside antibiotic,
used mostly to treat Gram-negative infections. However, it is not used
for Neisseria gonorrhoeae, Neisseria
meningitidis or Legionella
pneumophila infections. It is synthesized by Micromonospora, a genus of
Gram-positive bacteria widely distributed in water and soil. Like all
aminoglycosides, when gentamicin is given orally, it is not
systemically active because it is not absorbed to any
appreciable extent from the small intestine. It is useful in treatment
of infections caused by Pseudomonas
The tetracyclines consist of eight related antibiotics which
are all natural products of Streptomyces, although some can now
be produced semisynthetically or synthetically. Tetracycline, chlortetracycline
and doxycycline are the best known. The tetracyclines are
broad-spectrum antibiotics with a wide range of activity against both
Gram-positive and Gram-negative bacteria. Pseudomonas aeruginosa
is less sensitive but is generally susceptible to tetracycline
concentrations that are obtainable in the bladder. The tetracyclines
act by blocking the binding of aminoacyl tRNA to the A site on the
ribosome. Tetracyclines inhibit protein synthesis on isolated 70S or
80S (eucaryotic) ribosomes, and in both cases, their effect is on the
small ribosomal subunit. However, most bacteria possess an active
transport system for tetracycline that will allow intracellular
accumulation of the antibiotic at concentrations 50 times as great as
that in the medium. This greatly enhances its antibacterial
effectiveness and accounts for its specificity of action, since an
effective concentration cannot be accumulated in animal cells. Thus a
blood level of tetracycline which is harmless to
animal tissues can halt protein synthesis in invading bacteria.
The tetracyclines have a remarkably low toxicity and minimal side
effects when taken by animals. The combination of their broad spectrum
and low toxicity has led to their overuse and misuse by the medical
community and the wide-spread development of resistance has reduced
their effectiveness. Nonetheless,
tetracyclines still have some important uses, such as the use of doxycycline
in the treatment of Lyme disease.
Some newly discovered members of the tetracycline family (e.g.
chelocardin) have been shown to act by inserting into the bacterial
membrane, not by inhibiting protein synthesis.
tetracycline core structure. The tetracyclines are a large family of
antibiotics that were discovered as natural products of Streptomyces
bacteria beginning in the late 1940s. Tetracycline sparked the
development of many chemically altered
antibiotics and in doing so has proved to be one of the most important
discoveries made in the field of antibiotics. It is a classic
"broad-spectrum antibiotic" used to treat infections caused by
Gram-positive and Gram-negative bacteria and some protozoa.
semisynthetic tetracycline developed in the 1960s. It is frequently
used to treat chronic prostatitis, sinusitis, syphilis, chlamydia,
pelvic inflammatory disease, acne and rosacea. In addition, it is used
in the treatment and prophylaxis of anthrax and in prophylaxis against
It is also effective against Yersinia
pestis (the infectious agent of bubonic plague) and is
prescribed for the treatment of Lyme disease, ehrlichiosis and Rocky
Mountain spotted fever. Because doxycycline is one of the few
medications that is
effective in treating Rocky Mountain spotted fever (with the next best
alternative being chloramphenicol), it is indicated even for
use in children for this illness.
Chloramphenicol is a protein synthesis inhibitor that has a
spectrum of activity but it exerts a bacteriostatic effect. It is
effective against intracellular parasites such as the rickettsiae.
Unfortunately, aplastic anemia develops in a
small proportion (1/50,000)
of patients. Chloramphenicol was originally discovered and purified
the fermentation of a Streptomyces species, but currently it is
entirely by chemical synthesis. Chloramphenicol inhibits the bacterial
peptidyl transferase, thereby preventing the growth of the polypeptide
during protein synthesis.
structure of chloramphenicol
Chloramphenicol is entirely selective for 70S ribosomes and does not
affect 80S ribosomes. Its unfortunate toxicity towards the small
patients who receive it is in no way related to its effect on bacterial
protein synthesis. However, since mitochondria originated from
procaryotic cells and have 70S ribosomes, they are subject to
by some of the protein synthesis inhibitors including chloramphenicol.
This likely explains the toxicity of chloramphenicol. The eucaryotic
most likely to be inhibited by chloramphenicol are those undergoing
multiplication, thereby rapidly synthesizing mitochondria. Such cells
the blood forming cells of the bone marrow, the inhibition of which
present as aplastic anemia. Chloramphenicol was once a highly
antibiotic and a number of deaths from anemia occurred before its use
curtailed. Now it is seldom used in human medicine except in
situations (e.g. typhoid fever).
The macrolide family of antibiotics is characterized by
structures that contain large lactone rings linked through glycoside
bonds with amino sugars. The most important members of the group are erythromycin
and oleandomycin. Erythromycin is active against most
Gram-positive bacteria, Neisseria, Legionella and Haemophilus,
but not against the Enterobacteriaceae. Macrolides inhibit
bacterial protein synthesis by binding to the 50S ribosomal subunit.
Binding inhibits elongation of the protein by peptidyl transferase or
prevents translocation of the ribosome or both. Macrolides are
bacteriostatic for most bacteria but
are cidal for a few Gram-positive bacteria.
structure of a macrolide antibiotic, erythromycin.
shown above, is a subclass of macrolide antibiotics. Azithromycin is
one of the world's best-selling antibiotics. It is s derived from
erythromycin, but it differs chemically from erythromycin in that a
methyl-substituted nitrogen atom is incorporated into the lactone
ring, thus making the lactone ring 15-membered. Azithromycin is used to
treat certain bacterial infections, most often bacteria causing middle
ear infections, tonsillitis, throat infections, laryngitis, bronchitis,
pneumonia and sinusitis. It is also effective against certain sexually
transmitted diseases, such as non-gonococcal urethritis and cervicitis.
Lincomycin and clindamycin are a miscellaneous group
synthesis inhibitors with activity similar to the macrolides. Lincomycin
has activity against Gram-positive bacteria and some Gram-negative
bacteria (Neisseria, H. influenzae). Clindamycin is a
derivative of lincomycin with the same range of antimicrobial
activity, but it is considered more effective. It is frequently used as
a penicillin substitute and is effective against Gram-negative
anaerobes (e.g. Bacteroides).
is a lincosamide antibiotic. It is usually used to treat infections
with anaerobic bacteria but can also be used to treat some protozoal
diseases, such as malaria. It is a common topical treatment for acne,
and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA)
infections. The most severe common adverse effect of clindamycin is Clostridium difficile-associated
diarrhea (the most frequent cause of pseudomembranous colitis).
Although this side-effect occurs with almost all antibiotics, including
beta-lactam antibiotics, it is classically linked to clindamycin use.