Identification of novel inhibitors of bacterial translation elongation factors

Antimicrob Agents Chemother. 2005 Jan;49(1):131-6. doi: 10.1128/AAC.49.1.131-136.2005.


Bacterial elongation factor Tu (EF-Tu) and EF-Ts are interacting proteins involved in polypeptide chain elongation in protein biosynthesis. A novel scintillation proximity assay for the detection of inhibitors of EF-Tu and EF-Ts, as well as the interaction between them, was developed and used in a high-throughput screen of a chemical library. Several compounds from a variety of chemical series with inhibitory properties were identified, including certain indole dipeptides, benzimidazole amidines, 2-arylbenzimidazoles, N-substituted imidazoles, and N-substituted guanidines. The in vitro activities of these compounds were confirmed in a coupled bacterial transcription-translation assay. Several indole dipeptides were identified as inhibitors of bacterial translation, with compound 2 exhibiting a 50% inhibitory concentration of 14 microM and an MIC for S. aureus ATCC 29213 of 5.6 microg/ml. Structure-activity relationship studies around the dipeptidic indoles generated additional analogs with low micromolar MICs for both gram-negative and gram-positive bacteria. To assess the specificity of antibacterial action, these compounds were evaluated in a metabolic labeling assay with Staphylococcus aureus. Inhibition of translation, as well as limited effects on other macromolecular pathways for some of the analogs studied, indicated a possible contribution from a non-target-based antibacterial mechanism of action.

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology*
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Cocci / drug effects
  • Guanidines / chemistry
  • Guanidines / pharmacology
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Indoles / chemistry*
  • Macromolecular Substances / metabolism
  • Microbial Sensitivity Tests
  • Peptide Elongation Factor Tu / antagonists & inhibitors*
  • Peptide Elongation Factor Tu / metabolism
  • Peptide Elongation Factors / antagonists & inhibitors*
  • Peptide Elongation Factors / metabolism
  • Protein Biosynthesis / drug effects
  • Structure-Activity Relationship
  • Transcription, Genetic / drug effects


  • Anti-Bacterial Agents
  • Benzimidazoles
  • Dipeptides
  • Guanidines
  • Imidazoles
  • Indoles
  • Macromolecular Substances
  • Peptide Elongation Factors
  • elongation factor Ts
  • indole
  • Peptide Elongation Factor Tu