Preferential inhibition of protein synthesis by ketolide antibiotics in Haemophilus influenzae cells.
The ketolide antibiotics are semi-synthetic derivatives of erythromycin A with enhanced inhibitory activity in a wide variety of microorganisms. They have significantly lower MICs than the macrolide antibiotics for many Gram-positive organisms. Two ketolides, telithromycin and ABT-773, were tested for growth-inhibitory effects in Haemophilus influenzae. Both antibiotics increased the growth rate and reduced the viable cell number with IC(50) values of 1.5 microgram/ml. Protein synthesis was inhibited in cells with a similar IC(50) concentration (1.25 microgram/ml). Macrolide and ketolide antibiotics have been shown to have a second equivalent target for inhibition in cells, which is blocking the assembly of the 50S ribosomal subunit. Pulse and chase labeling assays were conducted to examine the effect of the ketolides on subunit formation in H. influenzae. Surprisingly, both antibiotics inhibited 50S and 30S subunit assembly to the same extent, with no specific effect of the compounds on 50S assembly. Over a range of antibiotic concentrations, 30S particle synthesis was diminished to the same extent as 50S formation. H. influenzae cells seem to have only one significant target for these antibiotics, and this may help to explain why these drugs are not more effective than the macrolides in preventing the growth of this microorganism.
Champney
W Scott
WS
Department of Biochemistry and Molecular Biology, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Tober
Craig L
CL
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis*; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D048628:Ketolides; D018942:Macrolides; D008826:Microbial Sensitivity Tests; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012270:Ribosomes / Q000187:drug effects
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D048628:Ketolides; D018942:Macrolides; D011500:Protein Synthesis Inhibitors; D004917:Erythromycin; C405499:cethromycin; C106791:telithromycin