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Aminoglycosides

Classification

The first aminoglycoside antibiotic was discovered in 1943 and named streptomycin [1]; later, it was found that it was just one of the many members of a large family of related antibiotics produced by various species of Streptomyces and Micromonospora. Aminoglycosides derived from the latter genus, such as gentamicin, are distinguished in their spelling by an "i" rather than a "y" in the suffix.

Structurally, most aminoglycosides consist of aminosugars linked to aminosubstituted cyclic polyalcohol (aminocyclitol). One antibiotic usually included with the group, spectinomycin, contains no aminoglycoside substituent and is properly regarded as a pure aminocyclitol.

Streptomycin is one of the members of Streptamines, while a second family of aminoglicosides was named 2-deoxystreptamines:

In addition to these compounds, there is a large group of atypical aminoglycosides, compounds that are of diverse microbial origin, structure, and biological activity (Ashimycin, Astromicin/Istamycin, Boholmycin, Kasugamycin, Myomycin, Spectinomycin, Trehalosamine, Validamycin).

General properties
The aminoglycosides are potent, broad-spectrum bactericidal agents that are very poorly absorbed when given orally and are therefore administered i.v. The spectrum includes most Gram-negative bacilli and staphylococci. They lack useful activity against streptococci and anaerobes, but the activity against streptococci can often be improved by using them in conjunction with penicillins, with which they interact synergically. Aminoglycosides penetrate poorly into mammalian cells and are of limited value in infections caused by intracellular bacteria. Some members of the group display important activity against Mycobacterium tuberculosis or Pseudomonas aeruginosa. All of them display considerable toxicity affecting both the ear and the kidney.

Mode of action
The biochemical mode of action of the aminoglycosides as antibacterials has long been a topic of great interest. One important experiment done in 1948 showed that streptomycin blocks enzyme induction in susceptible bacteria [2].

In vitro translation studies employing hybrids of sensitive and resistant ribosome subunits showed that streptomycin acts by binding to the 30S ribosome subunit [3-4]. This led to the investigation of the effects of streptomycin and other aminoglycosides on coding fidelity during translation, providing evidence for the active role of the 30S subunit in protein synthesis and the important finding that streptomycin and other aminoglycosides induce errors in translation [5]. Recent structural studies on the ribosome complexes has
confirmed the role of the ribosome in translation and the mechanism by which aminoglycosides perturbate it by binding to specific sites on the 30S subunit [6]. There is strong genetic and phenotypic evidence for translation misreading by aminoglycosides in living cells [7]. At subinhibitory concentrations aminoglycosides induce marked changes in the transcription in about 5% of the genes in susceptible bacteria [8]. The mechanism responsible is not known but may be due to the coupling between translation and transcription not previously identified.

Nomura et al. used disruption and reconstitution of ribosome particles from 16S rRNA and isolated R proteins to demonstrate the roles of the proteins RpsL (str) and RpsE (spc) in the determination of antibiotic resistance [9]; this confirmed the earlier genetic and phenotypic studies and ratified the role of R proteins in ribosome function. The three-dimensional structure analysis of streptomycin /ribosome complex identifies an interaction of the drug with both R proteins and rRNA [6].

Streptomycin binds to a ribosomal protein that with a single amino acid change became resistant to streptomycin. Aminoglycosides of the kanamycin and neomycin groups bind at a different site and are generally unaffected. Several effects of the binding of streptomycin and other aminoglycosides have been noted, including misreading of certain codons of mRNA resulting in the production of defective proteins, some of which may affect membrane integrity. Other studies indicate that the primary site of action lies in the formation of non-functioning initiation complexes, or inhibition of the translocation step in polypeptide synthesis. None of these hypotheses fully explains the potent bactericidal activity of aminoglycosides compared with other inhibitors of protein synthesis. The ability of the aminoglycosides to rapidly kill bacterial pathogens is an important attribute in their therapeutic use. This action is rather unexpected if we consider that most inhibitors of ribosome function act in a similar fashion to the aminoglycosides, by binding to target sequences within the 16S or 23S rRNAs and have bacteriostatic effects. The possibility that aminoglycosides (as distinct from other translation inhibitors) induce a process of programmed cell death (apoptosis) in bacteria [10] could provide an explanation.

Toxicity

The main toxic effects of aminoglycosides are ototoxicity and renal toxicity [11]. Streptomycin and other aminoglycosides target sensory hair cells of the inner ear and can lead to hair-cell degeneration and permanent loss; this occurs by an as yet undetermined mechanism and leads to irreparable hearing loss in up to 5% of patients on extended treatment with aminoglycosides [12].

From a therapeutic point of view, relatively little efforts have been tried to redesign aminoglycoside structure to reduce toxic responses, probably because good in vitro testing models have not been available. The analyses of structure–activity relationships between the inhibitory and toxicity responses of the aminoglycosides have provided few significant insights into the problem.

 


1. Schatz, A.; Bugie, E.; Waksman, S. A. Proc. Soc. Exp. Biol. Med. 1944, 55, 66–69.

2. Fitzgerald, R. J.; Bernheim, F.; Fitzgerald, D. B. J. Biol. Chem. 1948, 175, 195–200.

3. Davies, J. E. Proc. Natl. Acad. Sci. USA 1964, 51, 659–664.

4. Cox, E. C.; White, J. R.; Flaks, J. G. Proc. Natl. Acad. Sci. USA 1964, 51, 703–709.

5. Davies, J.; Gilbert, W.; Gorini, L. Proc. Natl. Acad. Sci. USA 1964, 51, 883–890.

6. Carter, A.; Clemons, W.; Broderson, D.; Morgan-Warren, R.; Wimberley, B.; Ramakrishnan, V. Nature 2000, 407, 340–348.

7. Edelmann, P.; Gallant, J. Cell 1977, 10, 131–137.

8. Goh, E.; Yim, G.; Tsui, W.; McClure, J.; Surette, M.; Davies, J. Proc. Natl. Acad. Sci. USA 2002, 99, 17025.

9. Nomura, M. Trends Biochem. Sci. 1997, 22, 275–279.

10. Engelberg-Kulka, H.; Sat, B.; Hazan, R. ASM News 2001, 67, 617–624.

11. Rougier F. C. D.; Maurin M,; Sedoglavic A.; Ducher M.; Corvaisier S.; Jeliffe R.; Maire P. Antimicrob. Agents Chemother. 2003, 47, 1010–1016.

12. Waguespack, J. R.; Ricci, A. J. J. Physiol. 2005, 567, 359–360.

 

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