TY - JOUR
T1 - Elucidating the Structural Requirement of Uridylpeptide Antibiotics for Antibacterial Activity
AU - Terasawa, Yuma
AU - Sataka, Chisato
AU - Sato, Toyotaka
AU - Yamamoto, Kazuki
AU - Fukushima, Yukari
AU - Nakajima, Chie
AU - Suzuki, Yasuhiko
AU - Katsuyama, Akira
AU - Matsumaru, Takanori
AU - Yakushiji, Fumika
AU - Yokota, Shin Ichi
AU - Ichikawa, Satoshi
N1 - Funding Information:
We thank Chihiro Inagaki, Kousuke Nakamura, and Naoto Tokoro for initial investigation for the synthesis of 2 . We are also thankful Dr. K. Nishiguchi and Dr. S. Arioka (Shionogi Co., Ltd.) for MraY expression and purification. This research was supported in part by JSPS KAKENHI Grant-in-Aid for Scientific Research (B) (grant numbers 16H05097 and 19H03345 to S.I.), Grant-in Aid for Scientific Research on Innovative Areas “Frontier Research on Chemical Communications” (nos. 18H04599 and 20H04757 to S.I.), JSPS KAKENHI Grant-in-Aid for Research for Young Scientist (grant number JP19K16648 to T.S.), Takeda Foundation, The Tokyo Biomedical Research Foundation and was partly supported by Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), funded by MEXT under “Support Program for Implementation of New Equipment Sharing System”, Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED under grant number JP18am0101093j0002, AMED under grant number JP19ak0101118h0001, Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) from the Ministry of Education, Culture, Sport, Science, and Technology in Japan, and MEXT for the Joint Research Program of the Research Center for Zoonosis Control, Hokkaido University.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/9/10
Y1 - 2020/9/10
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.0c00973
DO - 10.1021/acs.jmedchem.0c00973
M3 - Article
C2 - 32787111
AN - SCOPUS:85090869475
SN - 0022-2623
VL - 63
SP - 9803
EP - 9827
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -