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Targeting the Class A Carbapenemase GES-5 via Virtual Screening

The worldwide spread of β-lactamases able to hydrolyze last resort carbapenems contributes to the antibiotic resistance problem and menaces the successful antimicrobial treatment of clinically relevant pathogens. Class A carbapenemases include members of the KPC and GES families. While drugs against...

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Autores principales: Klein, Raphael, Cendron, Laura, Montanari, Martina, Bellio, Pierangelo, Celenza, Giuseppe, Maso, Lorenzo, Tondi, Donatella, Brenk, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072645/
https://www.ncbi.nlm.nih.gov/pubmed/32075131
http://dx.doi.org/10.3390/biom10020304
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author Klein, Raphael
Cendron, Laura
Montanari, Martina
Bellio, Pierangelo
Celenza, Giuseppe
Maso, Lorenzo
Tondi, Donatella
Brenk, Ruth
author_facet Klein, Raphael
Cendron, Laura
Montanari, Martina
Bellio, Pierangelo
Celenza, Giuseppe
Maso, Lorenzo
Tondi, Donatella
Brenk, Ruth
author_sort Klein, Raphael
collection PubMed
description The worldwide spread of β-lactamases able to hydrolyze last resort carbapenems contributes to the antibiotic resistance problem and menaces the successful antimicrobial treatment of clinically relevant pathogens. Class A carbapenemases include members of the KPC and GES families. While drugs against KPC-type carbapenemases have recently been approved, for GES-type enzymes, no inhibitors have yet been introduced in therapy. Thus, GES carbapenemases represent important drug targets. Here, we present an in silico screening against the most prevalent GES carbapenemase, GES-5, using a lead-like compound library of commercially available compounds. The most promising candidates were selected for in vitro validation in biochemical assays against recombinant GES-5 leading to four derivatives active as high micromolar competitive inhibitors. For the best inhibitors, the ability to inhibit KPC-2 was also evaluated. The discovered inhibitors constitute promising starting points for hit to lead optimization.
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spelling pubmed-70726452020-03-19 Targeting the Class A Carbapenemase GES-5 via Virtual Screening Klein, Raphael Cendron, Laura Montanari, Martina Bellio, Pierangelo Celenza, Giuseppe Maso, Lorenzo Tondi, Donatella Brenk, Ruth Biomolecules Article The worldwide spread of β-lactamases able to hydrolyze last resort carbapenems contributes to the antibiotic resistance problem and menaces the successful antimicrobial treatment of clinically relevant pathogens. Class A carbapenemases include members of the KPC and GES families. While drugs against KPC-type carbapenemases have recently been approved, for GES-type enzymes, no inhibitors have yet been introduced in therapy. Thus, GES carbapenemases represent important drug targets. Here, we present an in silico screening against the most prevalent GES carbapenemase, GES-5, using a lead-like compound library of commercially available compounds. The most promising candidates were selected for in vitro validation in biochemical assays against recombinant GES-5 leading to four derivatives active as high micromolar competitive inhibitors. For the best inhibitors, the ability to inhibit KPC-2 was also evaluated. The discovered inhibitors constitute promising starting points for hit to lead optimization. MDPI 2020-02-14 /pmc/articles/PMC7072645/ /pubmed/32075131 http://dx.doi.org/10.3390/biom10020304 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Klein, Raphael
Cendron, Laura
Montanari, Martina
Bellio, Pierangelo
Celenza, Giuseppe
Maso, Lorenzo
Tondi, Donatella
Brenk, Ruth
Targeting the Class A Carbapenemase GES-5 via Virtual Screening
title Targeting the Class A Carbapenemase GES-5 via Virtual Screening
title_full Targeting the Class A Carbapenemase GES-5 via Virtual Screening
title_fullStr Targeting the Class A Carbapenemase GES-5 via Virtual Screening
title_full_unstemmed Targeting the Class A Carbapenemase GES-5 via Virtual Screening
title_short Targeting the Class A Carbapenemase GES-5 via Virtual Screening
title_sort targeting the class a carbapenemase ges-5 via virtual screening
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072645/
https://www.ncbi.nlm.nih.gov/pubmed/32075131
http://dx.doi.org/10.3390/biom10020304
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