Telithromycin Inhibition of Protein Synthesis and 50S Ribosomal Subunit Formation in Streptococcus pneumoniae Cells

Abstract

The new ketolide antibiotic telithromycin (HMR3647) has been examined for inhibitory effects in cells of Streptococcus pneumoniae. The antibiotic caused a proportional decline in cell growth rate and viability with an IC(50) of 15 ng/ml. At a concentration of 7.5 ng/ml, protein synthesis in these cells was reduced by 50%. As seen in other organisms, this compound was also a very effective inhibitor of the formation of the 50S ribosomal subunit in growing cells. Pulse and chase labeling assays defined the reduced rate of 50S synthesis in antibiotic treated cells. At 7.5 ng/ml the rate was reduced to 50% of the control synthesis rate. An IC(50) of 15 ng/ml was found for the effect on this process. 30S ribosomal subunit formation was unaffected by the antibiotic. Inhibition of translation and 50S particle formation are equivalent targets for this antibiotic. The effects of telithromycin in S. pneumoniae are compared with those found in Staphylococcus aureus cells.

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

“…The IC 50 of 7.5 ng/ml found for inhibition of translation and 50S assembly is comparable to the IC 50 s of 5 ng/ml observed for cethromycin (9) and 15 ng/ml measured for telithromycin (10). The solithromycin IC 50 is consistent with MIC 50 values of 15 to 60 ng/ml reported in various studies of S. pneumoniae strains (8,(21)(22)(23)(24)(25).…”

“…Methicillin-susceptible Staphylococcus aureus (MSSA) strain RN1786 was obtained from Richard Novick (New York University), and a clinical isolate of methicillin-resistant S. aureus (MRSA) (strain A1024) was provided by Joyce Sutcliffe (Tetraphase Pharmaceuticals) (12). H. influenzae strain CDC G-79 (13) and S. pneumoniae strain ATCC 49619 (9,10) 175 Ci/mmol) were purchased from American Radiochemicals (St. Louis, MO) and MP Biomedical (Solon, OH), respectively. Solithromycin was provided by Cempra Pharmaceuticals (Chapel Hill, NC) and was dissolved at 1 mg/ml in acetic acid at a pH of 5.5.…”

“…Its site of binding to the Escherichia coli 50S subunit has been characterized (8). This interaction inhibits protein biosynthesis and should impair bacterial ribosomal subunit formation, much like with other ketolides (9)(10)(11). In this study, the mechanism of action of solithromycin was tested in three important human pathogens, Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae.…”

Telithromycin new product overview

“…Ketolides interact with the 50S ribosomal subunit near the peptidyl transferase site to inhibit the translation of rRNAs and to prevent the elongation step of protein synthesis. 27 Ketolides also interfere with protein synthesis earlier in the process by interacting with partially assembled 50S subunit precursors to block the formation of a functional 50S subunit. 27 Telithromycin binds to domains II and V of the 50S subunit on the 23S rRNA (Fig 2).…”

“…27 Ketolides also interfere with protein synthesis earlier in the process by interacting with partially assembled 50S subunit precursors to block the formation of a functional 50S subunit. 27 Telithromycin binds to domains II and V of the 50S subunit on the 23S rRNA (Fig 2). 28,29 …”