Cargando…

SarA based novel therapeutic candidate against Staphylococcus aureus associated with vascular graft infections

Staphylococcus aureus is a common pathogen seen in prosthetic vascular graft, leading to high morbidity and mortality. The virulence genes for severity of infections are under the control of global regulators. Staphylococcal accessory regulator A (SarA) a known master controller of biofilm formation...

Descripción completa

Detalles Bibliográficos
Autores principales: Arya, Rekha, Ravikumar, R., Santhosh, R. S., Princy, S. Adline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447123/
https://www.ncbi.nlm.nih.gov/pubmed/26074884
http://dx.doi.org/10.3389/fmicb.2015.00416
_version_ 1782373551033024512
author Arya, Rekha
Ravikumar, R.
Santhosh, R. S.
Princy, S. Adline
author_facet Arya, Rekha
Ravikumar, R.
Santhosh, R. S.
Princy, S. Adline
author_sort Arya, Rekha
collection PubMed
description Staphylococcus aureus is a common pathogen seen in prosthetic vascular graft, leading to high morbidity and mortality. The virulence genes for severity of infections are under the control of global regulators. Staphylococcal accessory regulator A (SarA) a known master controller of biofilm formation is an attractive target for the drug development. A structure based screening of lead compounds was employed for the identification of novel small molecule inhibitors targeted to interact to the DNA binding domain of the transcriptional activator, SarA and hinder its response over the control of genes that up-regulate the phenotype, biofilm. The top-hit SarA selective inhibitor, 4-[(2,4-diflurobenzyl)amino] cyclohexanol (SarABI) was further validated in-vitro for its efficacy. The SarABI was found to have MBIC(50)value of 200 μg/ml and also down-regulated the expression of the RNA effector, (RNAIII), Hemolysin (hld), and fibronectin-binding protein (fnbA). The anti-adherence property of SarABI on S. aureus invasion to the host epithelial cell lines (Hep-2) was examined where no significant attachment of S. aureus was observed. The SarABI inhibits the colonization of MDR S. aureus in animal model experiment significantly cohere to the molecular docking studies and in vitro experiments. So, we propose that the SarABI could be a novel substitute to overcome a higher degree of MDR S. aureus colonization on vascular graft.
format Online
Article
Text
id pubmed-4447123
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-44471232015-06-12 SarA based novel therapeutic candidate against Staphylococcus aureus associated with vascular graft infections Arya, Rekha Ravikumar, R. Santhosh, R. S. Princy, S. Adline Front Microbiol Microbiology Staphylococcus aureus is a common pathogen seen in prosthetic vascular graft, leading to high morbidity and mortality. The virulence genes for severity of infections are under the control of global regulators. Staphylococcal accessory regulator A (SarA) a known master controller of biofilm formation is an attractive target for the drug development. A structure based screening of lead compounds was employed for the identification of novel small molecule inhibitors targeted to interact to the DNA binding domain of the transcriptional activator, SarA and hinder its response over the control of genes that up-regulate the phenotype, biofilm. The top-hit SarA selective inhibitor, 4-[(2,4-diflurobenzyl)amino] cyclohexanol (SarABI) was further validated in-vitro for its efficacy. The SarABI was found to have MBIC(50)value of 200 μg/ml and also down-regulated the expression of the RNA effector, (RNAIII), Hemolysin (hld), and fibronectin-binding protein (fnbA). The anti-adherence property of SarABI on S. aureus invasion to the host epithelial cell lines (Hep-2) was examined where no significant attachment of S. aureus was observed. The SarABI inhibits the colonization of MDR S. aureus in animal model experiment significantly cohere to the molecular docking studies and in vitro experiments. So, we propose that the SarABI could be a novel substitute to overcome a higher degree of MDR S. aureus colonization on vascular graft. Frontiers Media S.A. 2015-05-06 /pmc/articles/PMC4447123/ /pubmed/26074884 http://dx.doi.org/10.3389/fmicb.2015.00416 Text en Copyright © 2015 Arya, Ravikumar, Santhosh and Princy. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Arya, Rekha
Ravikumar, R.
Santhosh, R. S.
Princy, S. Adline
SarA based novel therapeutic candidate against Staphylococcus aureus associated with vascular graft infections
title SarA based novel therapeutic candidate against Staphylococcus aureus associated with vascular graft infections
title_full SarA based novel therapeutic candidate against Staphylococcus aureus associated with vascular graft infections
title_fullStr SarA based novel therapeutic candidate against Staphylococcus aureus associated with vascular graft infections
title_full_unstemmed SarA based novel therapeutic candidate against Staphylococcus aureus associated with vascular graft infections
title_short SarA based novel therapeutic candidate against Staphylococcus aureus associated with vascular graft infections
title_sort sara based novel therapeutic candidate against staphylococcus aureus associated with vascular graft infections
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447123/
https://www.ncbi.nlm.nih.gov/pubmed/26074884
http://dx.doi.org/10.3389/fmicb.2015.00416
work_keys_str_mv AT aryarekha sarabasednoveltherapeuticcandidateagainststaphylococcusaureusassociatedwithvasculargraftinfections
AT ravikumarr sarabasednoveltherapeuticcandidateagainststaphylococcusaureusassociatedwithvasculargraftinfections
AT santhoshrs sarabasednoveltherapeuticcandidateagainststaphylococcusaureusassociatedwithvasculargraftinfections
AT princysadline sarabasednoveltherapeuticcandidateagainststaphylococcusaureusassociatedwithvasculargraftinfections