title: Characterization of a novel antibacterial agent that inhibits bacterial translation.
abstract: Bacterial protein synthesis is the target for several classes of established antibiotics. This report describes the characterization of a novel translation inhibitor produced by the soil bacterium Flexibacter. The dipeptide antibiotic TAN1057 A/B was synthesized and designated GS7128. As reported previously, TAN1057 inhibits protein synthesis in both Escherichia coli and Staphylococcus aureus, leaving transcription unaffected. Cell-free translation systems from E. coli were used to further dissect the mechanism of translational inhibition. Binding of mRNA to ribosomes was unaffected by the drug, whereas the initiation reaction was reduced. Elongation of translation was completely inhibited by GS7128. Detailed analysis showed that the peptidyl transferase reaction was strongly inhibited, whereas tRNA binding to both A- and P-site was unaffected. Selection and analysis of drug-resistant mutants of S. aureus suggests that drug uptake may be mediated by a dipeptide transport mechanism.
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D001419:Bacteria / Q000378:metabolism; D003470:Culture Media; D004151:Dipeptides / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D012360:RNA, Transfer, Phe / Q000378:metabolism; D011817:Rabbits; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D003470:Culture Media; D004151:Dipeptides; D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D012360:RNA, Transfer, Phe; C081415:TAN 1057A; C081416:TAN 1057B; D010458:Peptidyl Transferases