401. Characterization of a novel antibacterial agent that inhibits bacterial translation.
- Author
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Böddeker N, Bahador G, Gibbs C, Mabery E, Wolf J, Xu L, and Watson J
- Subjects
- Animals, Anti-Bacterial Agents biosynthesis, Anti-Bacterial Agents isolation & purification, Bacteria metabolism, Culture Media, Dipeptides biosynthesis, Dipeptides isolation & purification, Drug Resistance, Bacterial, Enzyme Inhibitors isolation & purification, Enzyme Inhibitors pharmacology, Escherichia coli drug effects, Escherichia coli genetics, Escherichia coli metabolism, In Vitro Techniques, Peptide Chain Elongation, Translational drug effects, Peptide Chain Initiation, Translational drug effects, Peptidyl Transferases antagonists & inhibitors, Protein Synthesis Inhibitors isolation & purification, Protein Synthesis Inhibitors pharmacology, RNA, Transfer, Phe metabolism, Rabbits, Staphylococcus aureus drug effects, Staphylococcus aureus genetics, Staphylococcus aureus metabolism, Anti-Bacterial Agents pharmacology, Dipeptides pharmacology, Protein Biosynthesis drug effects
- 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.
- Published
- 2002
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