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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...

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Autores principales: Hasan, Md Kamrul, El Qaidi, Samir, McDonald, Peter, Roy, Anuradha, Hardwidge, Philip R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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