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Chemical logic of MraY inhibition by antibacterial nucleoside natural products
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 pr...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606608/ https://www.ncbi.nlm.nih.gov/pubmed/31266949 http://dx.doi.org/10.1038/s41467-019-10957-9 |
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author | Mashalidis, Ellene H. Kaeser, Benjamin Terasawa, Yuma Katsuyama, Akira Kwon, Do-Yeon Lee, Kiyoun Hong, Jiyong Ichikawa, Satoshi Lee, Seok-Yong |
author_facet | Mashalidis, Ellene H. Kaeser, Benjamin Terasawa, Yuma Katsuyama, Akira Kwon, Do-Yeon Lee, Kiyoun Hong, Jiyong Ichikawa, Satoshi Lee, Seok-Yong |
author_sort | Mashalidis, Ellene H. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6606608 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-66066082019-07-05 Chemical logic of MraY inhibition by antibacterial nucleoside natural products Mashalidis, Ellene H. Kaeser, Benjamin Terasawa, Yuma Katsuyama, Akira Kwon, Do-Yeon Lee, Kiyoun Hong, Jiyong Ichikawa, Satoshi Lee, Seok-Yong Nat Commun Article 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. Nature Publishing Group UK 2019-07-02 /pmc/articles/PMC6606608/ /pubmed/31266949 http://dx.doi.org/10.1038/s41467-019-10957-9 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article 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 |
title | Chemical logic of MraY inhibition by antibacterial nucleoside natural products |
title_full | Chemical logic of MraY inhibition by antibacterial nucleoside natural products |
title_fullStr | Chemical logic of MraY inhibition by antibacterial nucleoside natural products |
title_full_unstemmed | Chemical logic of MraY inhibition by antibacterial nucleoside natural products |
title_short | Chemical logic of MraY inhibition by antibacterial nucleoside natural products |
title_sort | chemical logic of mray inhibition by antibacterial nucleoside natural products |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606608/ https://www.ncbi.nlm.nih.gov/pubmed/31266949 http://dx.doi.org/10.1038/s41467-019-10957-9 |
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