Discovery of Indolyl-containing Peptides As Novel Antibacterial Agents Targeting tryptophanyl-tRNA Synthetase

Background: There is an urgent need for antibiotics with novel structures and unexploited targets to counteract bacterial resistance. Methodology & results: Novel tryptophanyl-tRNA synthetase inhibitors were discovered based on virtual screening, surface plasmon resonance binding, enzymatic activity assay and antibacterial activity evaluation. Of the 29 peptide derivatives tested for antibacterial activity, some inhibited the growth of both Staphylococcus aureus and Staphylococcus epidermidis. A 13 and A 15 exhibited antibacterial activity against methicillin-resistant S. aureus NRS384 at an 8 μg/ml minimum inhibitory concentration. A 13 snugly docked into the active site, explaining its improved inhibitory activity. Conclusion: Our results provide us with new structural clues to develop more potent tryptophanyl-tRNA synthetase inhibitors and lay a solid foundation for future drug design efforts.