Inhibition of protein synthesis by streptogramins and related antibiotics

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.

The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics

“…3C) are adjacent to the macrolides and S B binding sites, it is conceivable that compounds acting upon these two sites can either compete or cooperate in binding to the ribosome. Streptogramins are known for their synergistic action (24,51). Such cooperativity makes evolutionary sense: The same microorganism produces both S A and S B components, and their mutually enhanced action should be highly beneficial for the antibiotic producer.…”

“…Nature has not ignored this opportunity when evolving ribosomal antibiotics. For example, streptogramin antibiotics, produced by several Streptomyces species, are secreted as a combination of two structurally distinct compounds that inhibit cell growth by acting upon the PTC and NPET (23,24). Streptogramin A (S A ) compounds are cyclic poly-unsaturated macrolactones that bind in the PTC, whereas type B streptogramins (S B ) compounds are cyclic depsipeptides that bind in the NPET (6,7,25).…”

Resistance to the tetracyclines and macrolide-lincosamide-streptogramin group of antibiotics and its genetic linkage – a review

“…Macrolides with mycarose sugars on the fifth carbon in the lactone ring, lincosamides and streptogramin A inhibit the peptidyl transferase reaction [10], whereas macrolides of the erythromycin group prevent the early events of peptide elongation, and streptogramin B blocks the exit tunnel through which the nascent peptide chains exit the ribosome, resulting in the release of incomplete peptides [10,11].The first described macrolide erythromycin has a moderately broad spectrum of activity, while newer semi-synthetic derivatives (e.g. clarithromycin and azithromycin) have a broader spectrum and are used in human medicine for the treatment of upper and lower respiratory tract infections, infections of the skin and soft tissue, sexually transmitted diseases, community-acquired pneumonia and atypical Mycobacterium infections.…”

Ecological approach of macrolide-lincosamides-streptogramin producing Actinomyces from Cuban soils

“…A biochemical alteration of the 50S subunit of the bacterial ribosome, namely N6-dimethylation of a single adenine residue at the position 2058 in 23S rRNA, confers resistance to all members belonging to the MLS group of antibiotics. The result is a reduction of affinity between the antibiotic and the ribosome and the inability of the drug to inhibit the synthesis of proteins in resistant microorganism's (Vining andStuttard 1995 andCocito et al 1997).…”