DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1508
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Figure 54–2. Effects of aminoglycosides on protein synthesis. A. Aminoglycoside (represented by red circles) binds to the 30S ribosomal
subunit and interferes with initiation of protein synthesis by fixing the 30S–50S ribosomal complex at the start codon (AUG) of mRNA.
As 30S–50S complexes downstream complete translation of mRNA and detach, the abnormal initiation complexes, so-called streptomycin
monosomes, accumulate, blocking further translation of the message. Aminoglycoside binding to the 30S subunit also causes misreading
of mRNA, leading to B, premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein
or C, incorporation of incorrect amino acids (indicated by the red X), resulting in the production of abnormal or nonfunctional proteins.
capacity to cause misreading, presumably owing to differences in
their affinities for specific ribosomal proteins. Although there
appears to be a strong correlation between bactericidal activity and
the ability to induce misreading (Hummel and Böck, 1989), it is not
clear whether misreading is the primary mechanism of aminoglycoside-induced
cell death.
The resulting aberrant proteins may be inserted into the cell
membrane, leading to altered permeability and further stimulation of
aminoglycoside transport (Busse et al., 1992). This phase of aminoglycoside
transport, termed energy-dependent phase II (EDP 2
), is
poorly understood; however, EDP 2
may link to disruption of the structure
of the cytoplasmic membrane, perhaps by the aberrant proteins.
This concept is consistent with the observed progression of the leakage
of small ions, followed by larger molecules and, eventually, by
proteins from the bacterial cell prior to aminoglycoside-induced
death. This progressive disruption of the cell envelope, as well as
other vital cell processes, may help to explain the lethal action of
aminoglycosides (Bryan, 1989).
Microbial Resistance to the Aminoglycosides. Bacteria
may be resistant to aminoglycosides because of failure
of the antibiotic to penetrate intracellularly, inactivation
of the drug by microbial enzymes, or low affinity of the
drug for the bacterial ribosome. Intrinsic resistance to
aminoglycosides may be caused by failure of the drug to
penetrate the cytoplasmic (inner) membrane. Penetration
of drug across the outer membrane of gram-negative
microorganisms into the periplasmic space can be slow,
but resistance on this basis is unimportant clinically.
Transport of aminoglycosides across the cytoplasmic
membrane is an oxygen-dependent active process.
Strictly anaerobic bacteria thus are resistant to these
drugs because they lack the necessary transport system.
X
Similarly, facultative bacteria are resistant when they are
grown under anaerobic conditions.
Clinically, drug inactivation is the most common
mechanism for acquired microbial resistance to aminoglycosides.
The genes encoding aminoglycoside-modifying
enzymes are acquired primarily by conjugation and transfer
of resistance plasmids (Davies, 1994) (Chapter 48).
These enzymes phosphorylate, adenylate, or acetylate specific
hydroxyl or amino groups (Figure 54–1). Amikacin
is a suitable substrate for only a few of these inactivating
enzymes (Figure 54–1); thus, strains that are resistant to
multiple other aminoglycosides tend to be susceptible to
amikacin. The metabolites of the aminoglycosides may
compete with the unaltered drug for transport across the
inner membrane, but they are incapable of binding effectively
to ribosomes and interfering with protein synthesis.
A significant percentage of clinical isolates of Enterococcus
faecalis and E. faecium are highly resistant to all aminoglycosides.
Infections caused by aminoglycoside-resistant
strains of enterococci can be especially difficult to treat
because of the loss of the synergistic bactericidal activity
between a penicillin or vancomycin and an aminoglycoside
(Spera and Farber, 1992; Vemuri and Zervos, 1993).
Resistance to gentamicin indicates cross-resistance
to tobramycin, amikacin, kanamycin, and netilmicin
because the inactivating enzyme is bifunctional and
can modify all these aminoglycosides. Owing to differences
in the chemical structures of streptomycin and
other aminoglycosides, this enzyme does not modify
streptomycin, which is inactivated by another enzyme;