Bacterial ribosomal subunit synthesis: a novel antibiotic target.
The continuing increase in antibiotic-resistant pathogenic bacterial has stimulated research on the development of new antimicrobial agents and the identification of new cellular targets. One such target is the sequence of assembly steps required for the formation of bacterial ribosomal subunits. A large number of different protein synthesis inhibitors which affect large subunit function also prevent the 50S particle from being formed in growing cells. These compounds include the macrolide and ketolide antibiotics as well as certain lincosamides, B-type streptogramins and several other structurally unrelated translational inhibitors. This review describes the activities of these compounds as inhibitors of 50S subunit formation. For most of these drugs, their inhibitory effect on particle synthesis is equivalent to their effect on translation. This new target is thus of equal importance to translational inhibition as a mechanism of action of these compounds. Features of the 50S subunit precursor particle as a target for these drugs are described. Finally a model is presented which accounts for this activity and predicts certain features of the substrate for erythromycin methylase activity in inducible cells. Antibiotics which target subunit formation preferentially are predicted to be important bactericidal agents.
Champney
W S
WS
Department of Biochemistry and Molecular Biology, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. champney@etsu.edu
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000187:drug effects*; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D048628:Ketolides; D018942:Macrolides; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D012269:Ribosomal Proteins / Q000096:biosynthesis / Q000187:drug effects*; D012270:Ribosomes / Q000187:drug effects* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D048628:Ketolides; D018942:Macrolides; D011500:Protein Synthesis Inhibitors; D012269:Ribosomal Proteins; D004917:Erythromycin; C405499:cethromycin; C106791:telithromycin