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Structural Analysis of Sortase A Inhibitors

Bacterial sortases are cysteine transpeptidases that regulate the covalent linkage of several surface protein virulence factors in Gram-positive bacteria. Virulence factors play significant roles in adhesion, invasion of host tissues, biofilm formation and immune evasion, mediating the bacterial pat...

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Autores principales: Nitulescu, Georgiana, Zanfirescu, Anca, Olaru, Octavian Tudorel, Nicorescu, Isabela Madalina, Nitulescu, George Mihai, Margina, Denisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272945/
https://www.ncbi.nlm.nih.gov/pubmed/27879666
http://dx.doi.org/10.3390/molecules21111591
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author Nitulescu, Georgiana
Zanfirescu, Anca
Olaru, Octavian Tudorel
Nicorescu, Isabela Madalina
Nitulescu, George Mihai
Margina, Denisa
author_facet Nitulescu, Georgiana
Zanfirescu, Anca
Olaru, Octavian Tudorel
Nicorescu, Isabela Madalina
Nitulescu, George Mihai
Margina, Denisa
author_sort Nitulescu, Georgiana
collection PubMed
description Bacterial sortases are cysteine transpeptidases that regulate the covalent linkage of several surface protein virulence factors in Gram-positive bacteria. Virulence factors play significant roles in adhesion, invasion of host tissues, biofilm formation and immune evasion, mediating the bacterial pathogenesis and infectivity. Therefore, sortases are emerging as important targets for the design of new anti-infective agents. We employed a computational study, based on structure derived descriptors and molecular fingerprints, in order to develop simple classification methods which could allow predicting low active or high active SrtA inhibitors. Our results indicate that a highly active SrtA inhibitor has a molecular weight ranging between 180 and 600, contains one up to four nitrogen atoms, up to three oxygen atoms and under 18 hydrogen atoms. Also the hydrogen acceptor number and the molecular flexibility, as assessed by the number of rotatable bounds, have emerged as the most relevant descriptors for SrtA affinity. The Bemis-Murcko scaffolding revealed favoured scaffolds as containing at least two ring structures bonded directly or merged in a condensed cycle. This data represent a valuable tool for identifying new potent SrtA inhibitors, potential anti-virulence agents targeted against Gram-positive bacteria, including multiresistant strains.
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spelling pubmed-62729452018-12-28 Structural Analysis of Sortase A Inhibitors Nitulescu, Georgiana Zanfirescu, Anca Olaru, Octavian Tudorel Nicorescu, Isabela Madalina Nitulescu, George Mihai Margina, Denisa Molecules Article Bacterial sortases are cysteine transpeptidases that regulate the covalent linkage of several surface protein virulence factors in Gram-positive bacteria. Virulence factors play significant roles in adhesion, invasion of host tissues, biofilm formation and immune evasion, mediating the bacterial pathogenesis and infectivity. Therefore, sortases are emerging as important targets for the design of new anti-infective agents. We employed a computational study, based on structure derived descriptors and molecular fingerprints, in order to develop simple classification methods which could allow predicting low active or high active SrtA inhibitors. Our results indicate that a highly active SrtA inhibitor has a molecular weight ranging between 180 and 600, contains one up to four nitrogen atoms, up to three oxygen atoms and under 18 hydrogen atoms. Also the hydrogen acceptor number and the molecular flexibility, as assessed by the number of rotatable bounds, have emerged as the most relevant descriptors for SrtA affinity. The Bemis-Murcko scaffolding revealed favoured scaffolds as containing at least two ring structures bonded directly or merged in a condensed cycle. This data represent a valuable tool for identifying new potent SrtA inhibitors, potential anti-virulence agents targeted against Gram-positive bacteria, including multiresistant strains. MDPI 2016-11-22 /pmc/articles/PMC6272945/ /pubmed/27879666 http://dx.doi.org/10.3390/molecules21111591 Text en © 2016 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
Nitulescu, Georgiana
Zanfirescu, Anca
Olaru, Octavian Tudorel
Nicorescu, Isabela Madalina
Nitulescu, George Mihai
Margina, Denisa
Structural Analysis of Sortase A Inhibitors
title Structural Analysis of Sortase A Inhibitors
title_full Structural Analysis of Sortase A Inhibitors
title_fullStr Structural Analysis of Sortase A Inhibitors
title_full_unstemmed Structural Analysis of Sortase A Inhibitors
title_short Structural Analysis of Sortase A Inhibitors
title_sort structural analysis of sortase a inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272945/
https://www.ncbi.nlm.nih.gov/pubmed/27879666
http://dx.doi.org/10.3390/molecules21111591
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