Structural basis for selectivity and toxicity of ribosomal antibiotics

Abstract

Ribosomal antibiotics must discriminate between bacterial and eukaryotic ribosomes to various extents. Despite major differences in bacterial and eukaryotic ribosome structure, a single nucleotide or amino acid determines the selectivity of drugs affecting protein synthesis. Analysis of resistance mutations in bacteria allows the prediction of whether cytoplasmic or mitochondrial ribosomes in eukaryotic cells will be sensitive to the drug. This has important implications for drug specificity and toxicity. Together with recent data on the structure of ribosomal subunits these data provide the basis for development of new ribosomal antibiotics by rationale drug design.

Fig. 1. Chemical structures of ribosomal antibiotics. (A) Common elements of 2-deoxystreptamine aminoglycosides to which expression of 1408G confers resistance. Rings I and II are common moieties of the aminoglycosides. Ring I carries an N6 amino group, ring II carries N1 and N3 amino groups, the linkage of ring III can vary. In the neomycin class ring III is connected to position 5 of ring II (4,5-disubstituted ring II), in the kanamycin class ring III is linked to position 6 of ring II (4,6-disubstituted ring II: gentamicin, amikacin, tobramycin, kanamycin). (B) Structure of aminoglycosides of the streptomycin family to which expression of RpsL 87 Gly confers resistance. Streptomycins are aminoglycoside antibiotics characterized by the presence of a cyclitol (R₁). (C) Chemical structures of antibiotics to which expression of 2058G confers resistance. Macrolides are composed of a minimum of two amino (R₃) and/or neutral sugars (R₂) attached to a lactone ring of variable size, most commercially available macrolides contain a 14-atom lacton ring (clarithromycin, roxithromycin, erythromycin) or a 15-atom lacton ring (azithromycin) structure; lincosamides (lincomycin, clindamycin) are alkyl derivates of proline and are devoid of a lactone ring; streptogramin B antibiotics (quinupristin, pristinamycin I, virginiamycin S, streptogramin B) are cyclic hexadepsipeptides, R₄ usually is pipecolic acid or one of its derivatives.