Elucidating the Structural Requirement of Uridylpeptide Antibiotics for Antibacterial Activity

J Med Chem. 2020 Sep 10;63(17):9803-9827. doi: 10.1021/acs.jmedchem.0c00973. Epub 2020 Aug 17.


The synthesis and biological evaluation of analogues of uridylpeptide antibiotics were described, and the molecular interaction between the 3'-hydroxy analogue of mureidomycin A (3'-hydroxymureidomycin A) and its target enzyme, phospho-MurNAc-pentapeptide transferase (MraY), was analyzed in detail. The structure-activity relationship (SAR) involving MraY inhibition suggests that the side chain at the urea-dipeptide moiety does not affect the MraY inhibition. However, the anti-Pseudomonas aeruginosa activity is in great contrast and the urea-dipeptide motif is a key contributor. It is also suggested that the nucleoside peptide permease NppA1A2BCD is responsible for the transport of 3'-hydroxymureidomycin A into the cytoplasm. A systematic SAR analysis of the urea-dipeptide moiety of 3'-hydroxymureidomycin A was further conducted and the antibacterial activity was determined. This study provides a guide for the rational design of analogues based on uridylpeptide antibiotics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / metabolism*
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Dipeptides / chemical synthesis
  • Dipeptides / metabolism*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / metabolism*
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Binding
  • Pseudomonas aeruginosa / drug effects
  • Sequence Alignment
  • Staphylococcus aureus / enzymology
  • Structure-Activity Relationship
  • Transferases (Other Substituted Phosphate Groups)
  • Transferases / antagonists & inhibitors
  • Transferases / chemistry
  • Transferases / metabolism
  • Urea / analogs & derivatives
  • Urea / metabolism
  • Uridine / analogs & derivatives*
  • Uridine / metabolism*


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Dipeptides
  • Enzyme Inhibitors
  • Urea
  • Transferases
  • Transferases (Other Substituted Phosphate Groups)
  • mraY protein, Bacteria
  • Uridine