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Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis
Bacterial resistance is an increasing threat to healthcare systems, highlighting the need for discovering new antibacterial agents. An established technique, fragment-based drug discovery, was used to target a bacterial enzyme Ddl involved in the biosynthesis of peptidoglycan. We assembled general a...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9718554/ https://www.ncbi.nlm.nih.gov/pubmed/36446617 http://dx.doi.org/10.1080/14756366.2022.2149745 |
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author | Proj, Matic Hrast, Martina Bajc, Gregor Frlan, Rok Meden, Anže Butala, Matej Gobec, Stanislav |
author_facet | Proj, Matic Hrast, Martina Bajc, Gregor Frlan, Rok Meden, Anže Butala, Matej Gobec, Stanislav |
author_sort | Proj, Matic |
collection | PubMed |
description | Bacterial resistance is an increasing threat to healthcare systems, highlighting the need for discovering new antibacterial agents. An established technique, fragment-based drug discovery, was used to target a bacterial enzyme Ddl involved in the biosynthesis of peptidoglycan. We assembled general and focused fragment libraries that were screened in a biochemical inhibition assay. Screening revealed a new fragment-hit inhibitor of DdlB with a Ki value of 20.7 ± 4.5 µM. Binding to the enzyme was confirmed by an orthogonal biophysical method, surface plasmon resonance, making the hit a promising starting point for fragment development. |
format | Online Article Text |
id | pubmed-9718554 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-97185542022-12-03 Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis Proj, Matic Hrast, Martina Bajc, Gregor Frlan, Rok Meden, Anže Butala, Matej Gobec, Stanislav J Enzyme Inhib Med Chem Research Paper Bacterial resistance is an increasing threat to healthcare systems, highlighting the need for discovering new antibacterial agents. An established technique, fragment-based drug discovery, was used to target a bacterial enzyme Ddl involved in the biosynthesis of peptidoglycan. We assembled general and focused fragment libraries that were screened in a biochemical inhibition assay. Screening revealed a new fragment-hit inhibitor of DdlB with a Ki value of 20.7 ± 4.5 µM. Binding to the enzyme was confirmed by an orthogonal biophysical method, surface plasmon resonance, making the hit a promising starting point for fragment development. Taylor & Francis 2022-11-29 /pmc/articles/PMC9718554/ /pubmed/36446617 http://dx.doi.org/10.1080/14756366.2022.2149745 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Paper Proj, Matic Hrast, Martina Bajc, Gregor Frlan, Rok Meden, Anže Butala, Matej Gobec, Stanislav Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis |
title | Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis |
title_full | Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis |
title_fullStr | Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis |
title_full_unstemmed | Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis |
title_short | Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis |
title_sort | discovery of a fragment hit compound targeting d-ala:d-ala ligase of bacterial peptidoglycan biosynthesis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9718554/ https://www.ncbi.nlm.nih.gov/pubmed/36446617 http://dx.doi.org/10.1080/14756366.2022.2149745 |
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