Use
Much of the literature on the mode of action of aminoglycosides has concentrated on streptomycin. However, the action of gentamicin and other deoxystreptamine-containing aminoglycosides is clearly not identical, since single-step, high-level resistance to streptomycin, which is due to a change in a specific protein (S12) of the 30S ribosomal subunit, does not extend to other aminoglycosides.
Elucidation of the mode of action of aminoglycosides has been complicated by the need to reconcile a variety of enigmatic observations:
Streptomycin and other aminoglycosides cause misreading of mRNA on the ribosome while paradoxically halting protein synthesis completely by interfering with the formation of functional initiation complexes.
Inhibition of protein synthesis by aminoglycosides leads not just to bacteristasis as with, for example, tetracycline or chloramphenicol, but also to rapid cell death.
Susceptible bacteria (but not those with resistant ribosomes) quickly become leaky to small molecules on exposure to the drug, apparently because of an effect on the cell membrane.
A complete understanding of these phenomena has not yet been achieved, but the situation is slowly becoming clearer. The two effects of aminoglycosides on initiation and misreading may be explained by a concentration-dependent effect on ribosomes engaged in the formation of the initiation complex and those in the process of chain elongation:16 in the presence of a sufficiently high concentration of drug, protein synthesis is completely halted once the mRNA is run off because reinitiation is blocked; under these circumstances there is little or no opportunity for misreading to occur. However, at concentrations at which only a proportion of the ribosomes can be blocked at initiation, some protein synthesis will take place and the opportunity for misreading will be provided.
The mechanism of misreading has been clarified by recent structural information on the interaction of streptomycin with the ribosome.13 Streptomycin binds near to the A site through strong interactions with four nucleotides in 16S rRNA and one residue in protein S12. This tight binding promotes a conformational change which stabilizes the so-called ram state in the ribosome which reduces the fidelity of translation by allowing non-cognate aminoacyl-tRNAs to bind easily to the A site.
The effects of aminoglycosides on membrane permeability, and the potent bactericidal activity of these compounds, remain enigmatic. However, the two phenomena may be related.17 The synthesis and subsequent insertion of misread proteins into the cytoplasmic membrane may lead to membrane leakiness and cell death.