Inhibition of Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureus Cells by 11 Different Ketolide Antibiotics

Abstract

Eleven structurally similar ketolide antibiotics were tested at a concentration of 1 microg/ml for their relative inhibitory effects on growth and ribosome activities in Staphylococcus aureus cells. Ten of the compounds examined had an inhibitory effect on protein synthesis at this concentration and eight of the 11 compounds were also effective inhibitors of the formation of the 50S ribosomal subunit. All of the drugs tested inhibited protein synthesis to a greater extent than they affected 50S subunit formation. The decline in growth rate and cell number was proportional to the effect on ribosome formation and function. The growth of an ermC erythromycin-resistant strain of S. aureus was also significantly inhibited by nine ketolide compounds, suggesting that they were not inducers of methylase gene expression. These inhibitory activities can be related to structural differences between these ketolide antibiotics.

Evernimicin (SCH27899) Inhibits both Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureus Cells

“…Evernimicin (SCH 27899) and its placebo were generously provided by T. Black of Schering-Plough Corp. Evernimicin was made as a stock solution at 160 g/ml in placebo and was diluted in placebo as needed. Cells were grown at 37°C in tryptic soy broth (TSB) in the presence and absence of evernimicin as described previously (7,8). The erythromycin-resistant strains were grown with erythromycin at 50 g/ml, and the MRSA organisms were grown with ampicillin at 50 g/ml.…”

“…Cell lysis and sucrose gradient sedimentation of ribosomal subunits were performed as described previously (7,8). The absorbance at 254 nm for each…”

“…Macrolide and ketolide antibiotics have equivalent inhibitory effects on both translation and 50S subunit formation in S. aureus (7,8). Since it has been suggested that evernimicin inhibits protein synthesis by interacting with the 50S subunit (Adrian and Klugman, 38th ICAAC), we decided to investigate its inhibitory effects on translation and subunit assembly in a systematic fashion.…”

“…At the end of the chase period, viable cell counts were measured by serial dilution of cells in A salts (18) followed by plating of 10 l on square TSB agar plates by the method of Jett et al (15). The colonies were counted after 48 h at 37°C.Cell lysis and sucrose gradient sedimentation of ribosomal subunits were performed as described previously (7,8). The absorbance at 254 nm for each…”

Effects of Escherichia coli Lipopolysaccharide on Telithromycin Pharmacokinetics in Rats: Inhibition of Metabolism via CYP3A

“…This alteration resulted in both improved pharmacokinetic properties and an improved spectrum of activity against community-acquired upper and lower respiratory tract pathogens compared to those of erythromycin (4). Telithromycin inhibits bacterial protein synthesis via two mechanisms, first by directly blocking the translation of mRNA and second by interfering with the assembly of new ribosomal units (5). Telithromycin has potent activities both in vitro and in vivo against common respiratory tract pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and group A beta-hemolytic streptococci, irrespective of their ␤-lactam or macrolide susceptibility (1).…”