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

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CHAPTER 54
NEOMYCIN B
AMINOGLYCOSIDES
STREPTOMYCIN
KANAMYCIN A
Mechanism of Action. The aminoglycoside antibiotics are
rapidly bactericidal. Bacterial killing is concentration
dependent: The higher the concentration, the greater is
the rate at which bacteria are killed. A post-antibiotic
effect, that is, residual bactericidal activity persisting
after the serum concentration has fallen below the minimum
inhibitory concentration (MIC), also is characteristic
of aminoglycoside antibiotics; the duration of
this effect also is concentration dependent. These properties
probably account for the efficacy of high-dose,
extended-interval dosing regimens of aminoglycosides.
Aminoglycosides diffuse through aqueous channels
formed by porin proteins in the outer membrane
of gram-negative bacteria to enter the periplasmic
space. Transport of aminoglycosides across the cytoplasmic
(inner) membrane depends on electron transport,
in part because of a requirement for a membrane
electrical potential (interior negative) to drive permeation
of these antibiotics. This phase of transport has
been termed energy-dependent phase I (EDP 1
). It is
rate limiting and can be blocked or inhibited by divalent
cations (e.g., Ca 2+ and Mg 2+ ), hyperosmolarity, a
reduction in pH, and anaerobic conditions. The last two
conditions impair the ability of the bacteria to maintain
the membrane potential, which is the driving force for
transport. Thus, the antimicrobial activity of aminoglycosides
is reduced markedly in the anaerobic environment
of an abscess, in hyperosmolar acidic urine, and
in other conditions that limit EDP 1
(Mingeot-Leclercq
et al., 1999).
Once inside the cell, aminoglycosides bind to
polysomes and interfere with protein synthesis by causing
misreading and premature termination of mRNA
translation (Figure 54–2).
The primary intracellular site of action of the aminoglycosides
is the 30S ribosomal subunit, which consists of 21 proteins and
a single 16S molecule of RNA. At least three of these ribosomal proteins,
and perhaps the 16S ribosomal RNA as well, contribute to the
streptomycin-binding site, and alterations of these molecules
markedly affect the binding and subsequent action of streptomycin.
For example, a single amino acid substitution of asparagine for
lysine at position 42 of the S 12
ribosomal protein prevents binding of
the drug; the resulting mutant is totally resistant to streptomycin.
Substitution of glutamine for lysine creates a mutant that actually
requires streptomycin for survival. The other aminoglycosides also
bind to the 30S ribosomal subunit; however, they also appear to bind
to several sites on the 50S ribosomal subunit (Davis, 1988).
Aminoglycosides disrupt the normal cycle of ribosomal function
by interfering, at least in part, with the initiation of protein synthesis,
leading to the accumulation of abnormal initiation complexes,
or streptomycin monosomes, shown schematically in Figure 54–2B
(Luzzatto et al., 1969). Aminoglycosides also cause misreading of
the mRNA template and incorporation of incorrect amino acids into
the growing polypeptide chains. Aminoglycosides vary in their