the enzyme dihydrofolate reduc

bacteria, 0.07 mM for protozoa, and 250 mM

for mammals. Thus, the drug can be used against bacteria
and protozoa at concentrations that do not harm humans.
This example of effi cacy is based on the relative
insensitivity of the host compared with bacterial targets.
In another example, both host cells and bacteria aresensitive to tetracycline. However,
unlike mammalian
cells, bacteria concentrate the antibiotic. As a result, tetracycline
is effective against even intracellular organisms
(e.g., chlamydiae).
The armamentarium of antimicrobials includes drugs
that affect the synthesis or function of every class of
microbial macromolecules. Extreme selectivity is achieved
when the biochemical target is absent in the host cells.
The best examples are the -lactam antibiotics (e.g., penicillin),
which affect the biosynthesis of the murein layer
of the bacterial cell wall (see Chapter 3). No comparable
structure exists in mammalian cells, which are therefore
totally insensitive to the action of these antibiotics. Nonetheless,
even -lactams can have undesirable side effects.
Some individuals cannot take them because they have
a strong allergic reaction. Also, administration of broadspectrum
-lactams can result in the destruction of the
normal intestinal microbiota. This effect can lead to colitis,
overgrowth by fungi, and other complications. Even a
nearly perfect antibiotic comes with a price.
HOW DO MICROBES CIRCUMVENT
THE ACTION OF ANTIBIOTICS?
The destructive power of antibiotics is so pervasive that
within a few years of their introduction, resistant organisms
can supplant susceptible ones. At what point in
the action of antibiotics does resistance come into play?
The action of antimicrobial drugs can be broken into a
sequence of three steps: First, the drugs must associate
with the bacteria and penetrate their envelope. Second,
they must be transported to an intracellular site of action.
Third, they must bind to their specifi c biochemical target.
Resistance to drugs can occur at each step. Microorganisms,
like sophisticated biochemists, have developed a
multitude of ways to become resistant. Resistance poses
a serious problem when it arises in a pathogenic microbe
capable of causing damage to human hosts. Following are
the clinically relevant mechanisms of resistance:
Synthesis of enzymes that break down the drug molecule
Chemical modifi cation of the drug that interferes with
its function
Prevention of access to the target site by inhibiting
uptake
Prevention of access to the target site by increasing
export of the drug from the microbial cell
Modifi cation of the target site
All these mechanisms have been recognized in clinical
pathogens, but the most common is the last one.
Some of the examples introduced in Chapter 3 are treated
more fully in the following paragraphs. A more extensive
list of mechanisms of antibacterial resistance is shown in
Table 5-1.
b-Lactams and Enzymes that
Inactivate Them
Chapter 3 summarized the effects of penicillins, cephalosporins,
and carbapenems on cell wall formation and their
consequences for bacterial survival. This group of drugs is
large, and for various