Elucidating the Structural Requirement of Uridylpeptide Antibiotics for Antibacterial Activity

Yuma Terasawa, Chisato Sataka, Toyotaka Sato, Kazuki Yamamoto, Yukari Fukushima, Chie Nakajima, Yasuhiko Suzuki, Akira Katsuyama, Takanori Matsumaru, Fumika Yakushiji, Shin Ichi Yokota, Satoshi Ichikawa

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)9803-9827
Number of pages25
JournalJournal of Medicinal Chemistry
Volume63
Issue number17
DOIs
Publication statusPublished - 2020 Sep 10
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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