Nine structurally similar macrolide antibiotics were tested at a concentration of 0.5 microg/ml for their relative inhibitory effects on ribosome functions in Staphylococcus aureus cells. Eight of the compounds examined inhibited protein synthesis at this concentration. Seven of the nine compounds were also effective in blocking formation of the 50S ribosomal subunit. Roxithromycin and 14-hydroxy clarithromycin inhibited protein synthesis to a greater extent than they affected 50S subunit formation. Conversely, the compound 11, 12-carbonate-3 deoxy-clarithromycin affected 50S assembly more than translation. Only clarithromycin had any effect on 30S ribosomal subunit assembly. The decline in growth rate and cell number was proportional to the effect on ribosome formation or function by each compound. These inhibitory activities can be related to structural differences between these macrolide antibiotics.
Three pairs of related macrolide antibiotics, differing at the 11,12 position of the macrolactone ring, were compared for effects on growth rate, cell viability, protein synthesis, and 50S ribosomal subunit formation in Staphylococcus aureus cells. For each parameter measured, the 11,12 carbonate-derivatized compound was more inhibitory compared with the corresponding 11,12-hydroxy antibiotic. Substitution at the 3-position of the ring was also important in the relative inhibition observed. The degree of inhibition found in two different growth media was proportional to the generation time of the cells. Inhibition of both protein synthesis and 50S subunit formation by each drug correlated well with the inhibition of cell viability. The results indicate that closure of the 11,12-hydroxyl groups in macrolide antibiotics with a carbonate substitution generates a more effective antimicrobial agent.
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