Binding of novel macrolide structures to macrolides-lincosamides-streptogramin B-resistant ribosomes inhibits protein synthesis and bacterial growth.
Dimethylation of adenine 2058 in 23S rRNA renders bacteria resistant to macrolides, lincosamides, and streptogramin B (MLS resistance), because the antibiotic binding site on the altered 50S ribosomal subunit is no longer accessible. We now report that certain 6-O-methyl-11,12-cyclic carbamate derivatives of erythromycin are able to bind to dimethylated MLS-resistant 50S ribosomal subunits, thus inhibiting protein synthesis and cell growth. One of these novel structures, an 11-deoxy-11-(carboxyamino)-6-O-methylerythromycin A 11,12-(cyclic ester) derivative, structure 1a, was studied in detail. It inhibited in vitro protein synthesis in extracts prepared from both susceptible and MLS-resistant Bacillus subtilis with 50% inhibitory concentrations of 0.4 and 20 microM, respectively. The derivative bound specifically to a single site on the 50S subunit of MLS-resistant ribosomes prepared from B. subtilis and Staphylococcus aureus, and no binding to 30S subunits was observed. The association rate constant of derivative 1a with sensitive and resistant ribosomes was 100- and 500-fold slower, respectively, than that of the parent compound, erythromycin, with sensitive ribosomes. The dissociation rate constant of 1a from sensitive and resistant ribosomes was 50- to 100-fold slower than the rate of erythromycin dissociation from sensitive ribosomes. Furthermore, 1a binding to sensitive 50S subunits led to induction of ermC and ermD, while binding to resistant 50S subunits did not, showing that perturbation of sensitive and resistant 50S subunit function by 1a differs. These data demonstrated that 1a is unique in its interaction with MLS-resistant ribosomes and that this interaction causes a novel allosteric perturbation of ribosome function.
Goldman
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Anti-infective Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Kadam
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SK
D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000235:genetics / Q000648:ultrastructure; D001419:Bacteria / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D001426:Bacterial Proteins / Q000096:biosynthesis*; D003864:Depression, Chemical; D004352:Drug Resistance, Microbial; D004917:Erythromycin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D055231:Lincosamides; D018942:Macrolides; D008826:Microbial Sensitivity Tests; D010957:Plasmids; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D014769:Virginiamycin / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D055231:Lincosamides; D018942:Macrolides; D014769:Virginiamycin; D004917:Erythromycin