Ketolides are the most recent generation of antimicrobials derived from the 14-membered ring macrolide, erythromycin A. The main structural feature that differentiates ketolides from erythromycin is the keto group, which replaces the L-cladinose moiety at position 3 of the macrolactone ring. The keto group bestows greater acid stability on the drugs, and enables them to bind to their ribosomal target without causing expression of MLS(B) resistance in inducible strains. Several ketolides are described here, including ABT 773 and telithromycin (HMR 3647), both of which possess a carbamate at C11/C12 of the macrolactone ring. In telithromycin, which is the first ketolide to be approved for clinical use, the carbamate is linked to an alkyl-aryl extension, which is responsible for the increased potency of this compound relative to macrolides. This review examines how the structural differences between macrolides and the new ketolides are related to their antimicrobial activities in inhibiting protein synthesis and blocking the assembly of new ribosomal subunits.

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.

The continuing increase in antibiotic-resistant pathogenic bacterial has stimulated research on the development of new antimicrobial agents and the identification of new cellular targets. One such target is the sequence of assembly steps required for the formation of bacterial ribosomal subunits. A large number of different protein synthesis inhibitors which affect large subunit function also prevent the 50S particle from being formed in growing cells. These compounds include the macrolide and ketolide antibiotics as well as certain lincosamides, B-type streptogramins and several other structurally unrelated translational inhibitors. This review describes the activities of these compounds as inhibitors of 50S subunit formation. For most of these drugs, their inhibitory effect on particle synthesis is equivalent to their effect on translation. This new target is thus of equal importance to translational inhibition as a mechanism of action of these compounds. Features of the 50S subunit precursor particle as a target for these drugs are described. Finally a model is presented which accounts for this activity and predicts certain features of the substrate for erythromycin methylase activity in inducible cells. Antibiotics which target subunit formation preferentially are predicted to be important bactericidal agents.

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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