Cargando…
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...
Autores principales: | , , , , , , , |
---|---|
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 |
_version_ | 1783506454763798528 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7072645 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT kleinraphael targetingtheclassacarbapenemaseges5viavirtualscreening AT cendronlaura targetingtheclassacarbapenemaseges5viavirtualscreening AT montanarimartina targetingtheclassacarbapenemaseges5viavirtualscreening AT belliopierangelo targetingtheclassacarbapenemaseges5viavirtualscreening AT celenzagiuseppe targetingtheclassacarbapenemaseges5viavirtualscreening AT masolorenzo targetingtheclassacarbapenemaseges5viavirtualscreening AT tondidonatella targetingtheclassacarbapenemaseges5viavirtualscreening AT brenkruth targetingtheclassacarbapenemaseges5viavirtualscreening |