Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / metabolism*
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Bacterial Proteins / antagonists & inhibitors
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Bacterial Proteins / chemistry
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Bacterial Proteins / metabolism
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Dipeptides / chemical synthesis
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Dipeptides / metabolism*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / metabolism*
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Microbial Sensitivity Tests
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Molecular Docking Simulation
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Molecular Structure
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Protein Binding
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Pseudomonas aeruginosa / drug effects
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Sequence Alignment
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Staphylococcus aureus / enzymology
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Structure-Activity Relationship
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Transferases (Other Substituted Phosphate Groups)
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Transferases / antagonists & inhibitors
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Transferases / chemistry
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Transferases / metabolism
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Urea / analogs & derivatives
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Urea / metabolism
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Uridine / analogs & derivatives*
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Uridine / metabolism*
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Dipeptides
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Enzyme Inhibitors
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Urea
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Transferases
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Transferases (Other Substituted Phosphate Groups)
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mraY protein, Bacteria
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Uridine