1. Elucidating the Structural Requirement of Uridylpeptide Antibiotics for Antibacterial Activity
- Author
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Akira Katsuyama, Yuma Terasawa, Shin-ichi Yokota, Yukari Fukushima, Fumika Yakushiji, Chie Nakajima, Kazuki Yamamoto, Toyotaka Sato, Takanori Matsumaru, Chisato Sataka, Yasuhiko Suzuki, and Satoshi Ichikawa
- Subjects
Staphylococcus aureus ,Transferases (Other Substituted Phosphate Groups) ,Microbial Sensitivity Tests ,01 natural sciences ,Structure-Activity Relationship ,03 medical and health sciences ,Bacterial Proteins ,Transferases ,Drug Discovery ,Urea ,Moiety ,Transferase ,Structure–activity relationship ,Amino Acid Sequence ,Enzyme Inhibitors ,Uridine ,Peptide sequence ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Molecular Structure ,Rational design ,Dipeptides ,Anti-Bacterial Agents ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Enzyme ,Biochemistry ,chemistry ,Pseudomonas aeruginosa ,Molecular Medicine ,Antibacterial activity ,Sequence Alignment ,Nucleoside ,Protein Binding - 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.
- Published
- 2020