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Chapter: Modern Pharmacology with Clinical Applications: Aminoglycoside Antibiotics

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Aminoglycoside Antibiotics: Mechanism of Antibacterial Action

The antibacterial actions of the aminoglycosides in-volve two possibly synergistic effects.

MECHANISM OF ANTIBACTERIAL ACTION

 

The antibacterial actions of the aminoglycosides in-volve two possibly synergistic effects. First, the posi-tively charged aminoglycoside binds to negatively charged sites on the outer bacterial membrane, thereby disrupting membrane integrity. It is likely that the aminoglycoside-induced bacterial outer membrane degradation accounts for the rapid concentration-dependent bactericidal effect of these compounds. Second, aminoglycosides bind to various sites on bacte-rial 30S ribosomal subunits, disrupting the initiation of protein synthesis and inducing errors in the translation of messenger RNA to peptides. They also bind to sites on bacterial 50S ribosomal subunits, although the sig-nificance of this binding is uncertain. In addition, they have a postantibiotic effect; that is, they continue to sup-press bacterial regrowth even after removal of the an-tibiotic from the bacterial microenvironment. It is likely that ribosome disruption accounts for this postantibi-otic activity.


The postantibiotic effect is characterized by pro-longed suppression of bacterial regrowth after the ini-tially high aminoglycoside concentration has fallen to a subinhibitory level. Perhaps resumption of bacterial ri-bosomal function requires the time-consuming synthe-sis of new ribosomes after their disruption by aminogly-cosides. The postantibiotic effect explains why aminoglycosides can be given in single daily doses de-spite their short half-life.

 

Penetration of aminoglycosides through the outer bacterial membrane occurs both by outer membrane disruption and by diffusion through outer membrane porins. Penetration through the inner bacterial mem-brane occurs in two phases. The first requires that the cytosol have a negative electron potential and therefore be inhibited by the presence of a low pH. The second phase depends on aerobic bacterial metabolism and therefore will be inhibited by low oxygen tension. The latter two observations are of considerable clinical rele-vance, since both a low pH and a low oxygen tension frequently occur in bacterial abscesses. Administration of β-lactam antibiotics will reverse the negative effects of both low pH and low oxygen tension on the ability of aminoglycosides to penetrate into bacteria; this ability accounts in part for the synergism that occurs between aminoglycoside and β-lactam antibiotic drugs.

 

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