570
Bacterial Pathogenesis, Molecular Basis of
the concept of many agents as ‘‘wonder
drugs’’ is quickly fading and is being re-
placed with the reality that we may, if we
have not done so already, be selecting for
‘‘super organisms’’ resistant to all avail-
able drugs. By way of example, strains
of methicillin-resistant
Staph. aureus
have
been identiFed, and for those unfortu-
nate individuals who are infected by such
strains, there are no viable antimicrobial
options available. Aside from the purely
scientiFc standpoint, an understanding of
how pathogens become resistant to an-
timicrobials is quickly becoming an area
of intense research owing to the global
threat that such super organisms would
pose.
In general, there are several mecha-
nisms that would lead to the acquisition of
resistance to an antimicrobial.
Alteration of the target.
An organism
could evolve to select for those individ-
uals who have altered the target of the
an
t
im
i
c
rob
i
a
lsoa
stor
end
e
rth
et
a
rg
e
t
insensitive to the drug. This is seen in a
number of cases including the transpep-
tidases, which are enzymes involved in
bacterial cell wall synthesis and are nor-
mally inhibited by penicillins by virtue of
the fact that they are capable of binding the
drug. Single amino acid changes within
the protein structure of these molecules
can render them insensitive to the drug
altogether or merely reduce their bind-
ing afFnity for the drug so as to decrease
their sensitivity. Other antimicrobials tar-
get the ribosomes, molecules essential for
protein synthesis by the cell. Single muta-
tions within subunits of this molecule can
also render it insensitive to various drugs
such as spectinomycin.
Overproduction of the target.
While not a
common mechanism, bacterial pathogens
could overproduce a target and effectively
increase the amount of drug required to
be effective.
ModiFcation of the antimicrobial.
This
is a common mechanism and is easily
exempliFed by the bacterial
β
-lactamases.
These enzymes hydrolyze the lactam ring
component of various
β
-lactam antibiotics
(e.g. penicillin) to inactivate the drug.
A variation on this mechanism is the
addition of an acetyl moiety onto the
structure
of
chloramphenicol,
thereby
rendering it inactive.
Interfering with the accessibility of a target to
an antimicrobial.
Anumberofpotent
ia
l
mechanisms would fall into this category.
Given that the membrane is the primary
barrier between the bacterium and its
external environment, alteration of the per-
meability of the membrane would affect
the ability of certain lipophilic antimicro-
bials to enter the cell. This alteration in
permeability could be achieved by altering
the composition of the lipid bilayer. An-
other mechanism makes use of speciFc
transporter systems that many bacteria
maintain to speciFcally export antibiotics
out of the bacterial cell. A wide variety
of these so-called drug efflux pumps have
been described for many organisms (e.g.
P. aeruginosa
). It should be noted that
other more general efflux systems have
been described for some organisms. The
mtr
locus of
N. gonorrhoeae
is such an
example.
Production of new enzymes to bypass the
targeted site.
Some bacteria are able to
synthesize new enzymes that can carry out
asp
e
c
iF
cfun
c
t
i
onbu
tth
a
th
a
v
eas
i
g
-
niFcantly decreased afFnity for a speciFc
antibiotic.
An interesting mechanism for drug re-
sistance may also be available to those
pathogens that are capable of growing
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