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Title: Chemical logic of MraY inhibition by antibacterial nucleoside natural products

Abstract

Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design.

Authors:
 [1];  [1];  [2]; ORCiD logo [2];  [3];  [4]; ORCiD logo [3];  [2]; ORCiD logo [1]
  1. Duke Univ. Medical Center, Durham, NC (United States)
  2. Hokkaido Univ., Sapporo (Japan)
  3. Duke Univ., Durham, NC (United States)
  4. The Catholic Univ. of Korea, Bucheon (Korea)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); Japan Society for the Promotion of Science (JSPS); Astellas Foundation for Research on Metabolic Disorders; Ministry of Education, Culture, Sports, Science and Technology (MEXT); Japan Agency for Medical Research and Development (AMED)
OSTI Identifier:
1544864
Grant/Contract Number:  
[R01GM120594; 16H05097; 18H04599; 19H03345; P30 GM124165; S10 RR029205]
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
[ Journal Volume: 10; Journal Issue: 1]; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Antibiotics; Transferases; X-ray crystallography

Citation Formats

Mashalidis, Ellene H., Kaeser, Benjamin, Terasawa, Yuma, Katsuyama, Akira, Kwon, Do-Yeon, Lee, Kiyoun, Hong, Jiyong, Ichikawa, Satoshi, and Lee, Seok-Yong. Chemical logic of MraY inhibition by antibacterial nucleoside natural products. United States: N. p., 2019. Web. doi:10.1038/s41467-019-10957-9.
Mashalidis, Ellene H., Kaeser, Benjamin, Terasawa, Yuma, Katsuyama, Akira, Kwon, Do-Yeon, Lee, Kiyoun, Hong, Jiyong, Ichikawa, Satoshi, & Lee, Seok-Yong. Chemical logic of MraY inhibition by antibacterial nucleoside natural products. United States. doi:10.1038/s41467-019-10957-9.
Mashalidis, Ellene H., Kaeser, Benjamin, Terasawa, Yuma, Katsuyama, Akira, Kwon, Do-Yeon, Lee, Kiyoun, Hong, Jiyong, Ichikawa, Satoshi, and Lee, Seok-Yong. Tue . "Chemical logic of MraY inhibition by antibacterial nucleoside natural products". United States. doi:10.1038/s41467-019-10957-9. https://www.osti.gov/servlets/purl/1544864.
@article{osti_1544864,
title = {Chemical logic of MraY inhibition by antibacterial nucleoside natural products},
author = {Mashalidis, Ellene H. and Kaeser, Benjamin and Terasawa, Yuma and Katsuyama, Akira and Kwon, Do-Yeon and Lee, Kiyoun and Hong, Jiyong and Ichikawa, Satoshi and Lee, Seok-Yong},
abstractNote = {Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design.},
doi = {10.1038/s41467-019-10957-9},
journal = {Nature Communications},
number = [1],
volume = [10],
place = {United States},
year = {2019},
month = {7}
}

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