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Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases
We are interested in identifying and characterizing small molecule inhibitors of bacterial virulence factors for their potential use as anti-virulence inhibitors. We identified from high-throughput screening assays a potential activity for avasimibe, a previously characterized acyl-coenzyme A: chole...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953086/ https://www.ncbi.nlm.nih.gov/pubmed/35335693 http://dx.doi.org/10.3390/pathogens11030370 |
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author | Hasan, Md Kamrul El Qaidi, Samir McDonald, Peter Roy, Anuradha Hardwidge, Philip R. |
author_facet | Hasan, Md Kamrul El Qaidi, Samir McDonald, Peter Roy, Anuradha Hardwidge, Philip R. |
author_sort | Hasan, Md Kamrul |
collection | PubMed |
description | We are interested in identifying and characterizing small molecule inhibitors of bacterial virulence factors for their potential use as anti-virulence inhibitors. We identified from high-throughput screening assays a potential activity for avasimibe, a previously characterized acyl-coenzyme A: cholesterol acyltransferase inhibitor, in inhibiting the NleB and SseK arginine glycosyltransferases from Escherichia coli and Salmonella enterica, respectively. Avasimibe inhibited the activity of the Citrobacter rodentium NleB, E. coli NleB1, and S. enterica SseK1 enzymes, without affecting the activity of the human serine/threonine N-acetylglucosamine (O-GlcNAc) transferase. Avasimibe was not toxic to mammalian cells at up to 200 µM and was neither bacteriostatic nor bactericidal at concentrations of up to 125 µM. Doses of 10 µM avasimibe were sufficient to reduce S. enterica abundance in RAW264.7 macrophage-like cells, and intraperitoneal injection of avasimibe significantly reduced C. rodentium survival in mice, regardless of whether the avasimibe was administered pre- or post-infection. We propose that avasimibe or related derivates created using synthetic chemistry may have utility in preventing or treating bacterial infections by inhibiting arginine glycosyltransferases that are important to virulence. |
format | Online Article Text |
id | pubmed-8953086 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89530862022-03-26 Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases Hasan, Md Kamrul El Qaidi, Samir McDonald, Peter Roy, Anuradha Hardwidge, Philip R. Pathogens Article We are interested in identifying and characterizing small molecule inhibitors of bacterial virulence factors for their potential use as anti-virulence inhibitors. We identified from high-throughput screening assays a potential activity for avasimibe, a previously characterized acyl-coenzyme A: cholesterol acyltransferase inhibitor, in inhibiting the NleB and SseK arginine glycosyltransferases from Escherichia coli and Salmonella enterica, respectively. Avasimibe inhibited the activity of the Citrobacter rodentium NleB, E. coli NleB1, and S. enterica SseK1 enzymes, without affecting the activity of the human serine/threonine N-acetylglucosamine (O-GlcNAc) transferase. Avasimibe was not toxic to mammalian cells at up to 200 µM and was neither bacteriostatic nor bactericidal at concentrations of up to 125 µM. Doses of 10 µM avasimibe were sufficient to reduce S. enterica abundance in RAW264.7 macrophage-like cells, and intraperitoneal injection of avasimibe significantly reduced C. rodentium survival in mice, regardless of whether the avasimibe was administered pre- or post-infection. We propose that avasimibe or related derivates created using synthetic chemistry may have utility in preventing or treating bacterial infections by inhibiting arginine glycosyltransferases that are important to virulence. MDPI 2022-03-17 /pmc/articles/PMC8953086/ /pubmed/35335693 http://dx.doi.org/10.3390/pathogens11030370 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hasan, Md Kamrul El Qaidi, Samir McDonald, Peter Roy, Anuradha Hardwidge, Philip R. Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases |
title | Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases |
title_full | Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases |
title_fullStr | Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases |
title_full_unstemmed | Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases |
title_short | Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases |
title_sort | repurposing avasimibe to inhibit bacterial glycosyltransferases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953086/ https://www.ncbi.nlm.nih.gov/pubmed/35335693 http://dx.doi.org/10.3390/pathogens11030370 |
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