INHIBITION OF PROTEIN-SYNTHESIS BY STREPTOGRAMINS AND RELATED ANTIBIOTICS

The streptogramins and related antibiotics (the lincosamides and macro lides) (MLS) are important inhibitors of bacterial protein synthesis. The key reaction in this process is the formation of a peptide bond be tween the growing peptide chain (peptidyl-tRNA) linked to the P-site o f the 50S ribosome and aminoacyl-tRNA linked to the A site. This react ion is catalysed by the peptidyl transferase catalytic centre of the 5 0S ribosome. Type A and B streptogramins in particular have been shown to block this reaction through the inhibition of substrate attachment to the A and P sites and inhibition of peptide chain elongation. Syne rgy between type A and B components results from conformational change s imposed upon the peptidyl transferase centre by type A compounds and by inhibition of both early and late stages of protein synthesis. The conformational change increases ribosomal affinity for type B strepto gramins. Microbial resistance to the MLSB antibiotics is largely attri butable to mutations of rRNA bases, producing conformational changes i n the peptidyl transferase centre. This can result in resistance to a single inhibitor or to a group of antibiotics (MLSB). The activity of type A streptogramin is retained thus explaining the improved inhibito ry action of the combined streptogramins against macrolide and lincosa mide-resistant strains. However, the development of resistance to the streptogramins may be less of a problem because of the synergic effect of type A and B compounds which has also been demonstrated in strains resistant to MLSB i.e., high level resistance to the combined strepto gramins is only likely when type A streptogramin resistance determinan ts are present along with type B streptogramin resistance determinants .