Erythromycins peptidyltransferase inhibition

Macrolides bind to the SOS ribosomal subunit of bacteria but not to the SOS mammalian ribosome this accounts for its selective toxicity. Binding to the ribosome occurs at a site near peptidyltransferase, with a resultant inhibition of translocation, peptide bond formation, and release of oligopeptidyl tRNA. However, unlike chloramphenicol, the macrolides do not inhibit protein synthesis by intact mitochondria, and this suggests that the mitochondrial membrane is not permeable to erythromycin. 

On the other hand, the inhibitory effect of erythromycin, a 14-membered-ring macrolide, on such a peptidyltransferase reaction is markedly diminished in terms of the character of a substrate. Erythromycin inhibits poly(A)-dependent polymerization of a transferred substrate such as lysine residue linked to tRNA but not other oligonucleotide-dependent polymerization of an amino acid linked either to tRNA or to oligonucleotides such as CACCA and UACCA. It has been shown that the transfer of A-acylaminoacyl residues to puromycin (puromycin reaction) is usually stimulated by erythromycin [88, 89, 95]. Igarashi et al. [96] have also confirmed these findings. That is to say, they found that erythromycin inhibits the release of a deacylated tRNA from the P site of ribosome. The release of such a deacylated tRNA from the P site and the translocation of peptidyl-tRNA from the A site to the P site of ribosome occurs concomitantly when EF-G catalyzes the GTP-dependent movement of the ribosome and the codon-anticodon-linked mRNA-peptidyl-tRNA complex. 

Menninger and Otto [101] proposed a major inhibitory mechanism common to probably all macrolide antibiotics. In E. coli mutants with temperature-sensitive peptidyl-tRNA hydrolase (aminoacyl-tRNA hydrolase EC 3.1.1.29), they observed that peptidyl-tRNA accumulates at a nonpermissive temperature (40°C) and that the cells die. The accumulation at a high temperature was enhanced when the cells were pretreated with erythromycin, carbomycin, or spiramycin at doses sufficient to inhibit protein synthesis in wild-type cells but not sufficient to kill either mutant or wild-type cells at the permissive temperature (30°C). Based on their observations, they suggested that stimulated dissociation of peptidyl-tRNA from ribosomes is the major mechanism of action of macrolide antibiotics. Their observations agree with recent results showing that a macrolide antibiotic binds to peptidyltransferase in ribosome. 

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