Structure–Activity Relationships for Six Ketolide Antibiotics

Abstract

Six structurally related 3-keto-substituted macrolide antibiotics (ketolides) were compared for concentration-dependent inhibitory effects on growth rate, viable cell number, and protein synthesis rates in Staphylococcus aureus cells. Inhibitory effects on 50S ribosomal subunit formation were also examined, as this is a second target for these antibiotics. A concentration range of 0.01 to 0.1 μg/ml was tested. An IC₅₀ for inhibition of translation and 50S synthesis was measured for each compound, to relate structural features to inhibitory activity. ABT-773 was the most effective of the six compounds tested with an IC₅₀= 0.035 μg/ml. HMR 3004 was almost as effective with an IC₅₀= 0.05 μg/ml. Two 2-fluoroketolides (HMR 3562 and HMR 3787) were equivalent in their inhibitory activity with an IC₅₀= 0.06 μg/ml. Telithromycin (HMR 3647) had an IC₅₀= 0.08 μg/ml, and HMR 3832 was least effective with an IC₅₀= 0.11 μg/ml. Each antibiotic had an equivalent inhibitory effect on translation and 50S subunit formation. These results indicate specific structural features of these antimicrobial agents, which contribute to defined inhibitory activities against susceptible organisms.