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The continuing increase in antibiotic-resistant microorganisms is driving the search for new antibiotic targets and improved antimicrobial agents. Ketolides are semisynthetic derivatives of macrolide antibiotics, which are effective against certain resistant organisms. Solithromycin (CEM-101) is a novel fluoroketolide with improved antimicrobial effectiveness. This compound binds to the large 50S subunit of the ribosome and inhibits protein biosynthesis. Like other ketolides, it should impair bacterial ribosomal subunit formation. This mechanism of action was examined in strains ofStreptococcus pneumoniae ,Staphylococcus aureus , andHaemophilus influenzae . The mean 50% inhibitory concentrations (IC50 s) for solithromycin inhibition of cell viability, protein synthesis, and growth rate were 7.5, 40, and 125 ng/ml forStreptococcus pneumoniae ,Staphylococcus aureus , andHaemophilus influenzae , respectively. The net formation of the 50S subunit was reduced in all three organisms, with IC50 s similar to those given above. The rates of 50S subunit formation measured by a pulse-chase labeling procedure were reduced by 75% in cells growing at the IC50 of solithromycin. Turnover of 23S rRNA was stimulated by solithromycin as well. Solithromycin was found to be a particularly effective antimicrobial agent, with IC50 s comparable to those of telithromycin and significantly better than those of azithromycin and clarithromycin in these three microorganisms.

Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae