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Inhibition of protein synthesis by streptogramins and related antibiotics
C Cocito1, M Di Giambattista, E Nyssen
1Histology Department, University of Louvain, Medical School, Brussels, Belgium.
Abstract:
The streptogramins and related antibiotics (the lincosamides and macrolides) (MLS) are important inhibitors of bacterial protein synthesis. The key reaction in this process is the formation of a peptide bond between the growing peptide chain (peptidyl-tRNA) linked to the P-site of the 50S ribosome and aminoacyl-tRNA linked to the A site. This reaction is catalysed by the peptidyl transferase catalytic centre of the 50S 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. Synergy between type A and B components results from conformational changes 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 streptogramins. Microbial resistance to the MLSB antibiotics is largely attributable to mutations of rRNA bases, producing conformational changes in 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 inhibitory action of the combined streptogramins against macrolide and lincosamide-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 streptogramins is only likely when type A streptogramin resistance determinants are present along with type B streptogramin resistance determinants.
Insights
Streptogramins, lincosamides, and macrolides inhibit bacterial protein synthesis. Synergy between type A and B streptogramins enhances activity against resistant strains, potentially mitigating resistance development.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- Streptogramins, lincosamides, and macrolides (MLSB) are crucial antibiotics targeting bacterial protein synthesis.
- Bacterial protein synthesis involves peptide bond formation catalyzed by the 50S ribosomal subunit's peptidyl transferase center.
- Type A and B streptogramins inhibit this process by blocking substrate binding and peptide elongation.
Purpose of the Study:
- To elucidate the synergistic mechanism of type A and B streptogramins in inhibiting bacterial protein synthesis.
- To understand how this synergy impacts efficacy against antibiotic-resistant strains.
- To assess the potential for resistance development to combined streptogramins.
Main Methods:
- The study focuses on the molecular interactions between streptogramins and the 50S ribosomal subunit.
- It examines the effects of type A and B streptogramins on substrate binding and peptide elongation.
- Resistance mechanisms, including rRNA mutations, are analyzed in relation to antibiotic efficacy.
Main Results:
- Type A streptogramins induce conformational changes in the peptidyl transferase center, enhancing binding of type B streptogramins.
- This synergy effectively inhibits protein synthesis, even in strains resistant to individual MLSB antibiotics.
- Resistance to combined streptogramins requires the presence of resistance determinants for both type A and type B components.
Conclusions:
- The synergistic action of type A and B streptogramins provides a powerful strategy against bacterial protein synthesis.
- This combination demonstrates significant activity against strains exhibiting resistance to macrolides and lincosamides.
- The dual requirement for resistance determinants suggests a lower likelihood of widespread resistance to combined streptogramins.