Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Journal of the Brazilian Chemical Society (Online) |
Texto Completo: | http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532018000200297 |
Resumo: | Biofilms are widely present in many human chronic infections, often more resistant to treatment with antibiotics. Bacterial diguanylate cyclases (DGCs) synthesize cyclic dimeric guanosine monophosphate (c-di-GMP) from two guanosine-5'-triphosphate (GTP) molecules. c-di-GMP is a central second messenger controlling biofilm formation, turning this class of enzymes an attractive target to prevent and disrupt biofilms of pathogenic bacteria. Here, we apply an in silico ligand- and target-based hybrid method to screen potential DGC inhibitors from an FDA-approved drug databank. Mass spectrometry assays confirmed that seven screened compounds selectively bound to the GTP active site of P. aeruginosa WspR GGDEF domain. Four out of those, including the anti-inflammatory sulfasalazine and the anti-hypertensive eprosartan, inhibited distinct DGCs (P. aeruginosa WspR and E. coli YdeH) in the micromolar range. Sulfasalazine and eprosartan reduced aggregation in solution of E. coli overexpressing WspR or YdeH. Similar anti-aggregation effects were also observed for sulfasalazine-related anti-inflammatory drugs sulfadiazine and sulfathiazole, the latter a previously described anti-biofilm agent. The optimized pharmacokinetic properties and toxicological profiles of the DGC inhibitors could be promising candidates for new anti-microbial agents based on the drug reposition strategy. |
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Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclasesc-di-GMPdiguanylate cyclase enzymesbacterial biofilmvirtual screeningdrug repositioningBiofilms are widely present in many human chronic infections, often more resistant to treatment with antibiotics. Bacterial diguanylate cyclases (DGCs) synthesize cyclic dimeric guanosine monophosphate (c-di-GMP) from two guanosine-5'-triphosphate (GTP) molecules. c-di-GMP is a central second messenger controlling biofilm formation, turning this class of enzymes an attractive target to prevent and disrupt biofilms of pathogenic bacteria. Here, we apply an in silico ligand- and target-based hybrid method to screen potential DGC inhibitors from an FDA-approved drug databank. Mass spectrometry assays confirmed that seven screened compounds selectively bound to the GTP active site of P. aeruginosa WspR GGDEF domain. Four out of those, including the anti-inflammatory sulfasalazine and the anti-hypertensive eprosartan, inhibited distinct DGCs (P. aeruginosa WspR and E. coli YdeH) in the micromolar range. Sulfasalazine and eprosartan reduced aggregation in solution of E. coli overexpressing WspR or YdeH. Similar anti-aggregation effects were also observed for sulfasalazine-related anti-inflammatory drugs sulfadiazine and sulfathiazole, the latter a previously described anti-biofilm agent. The optimized pharmacokinetic properties and toxicological profiles of the DGC inhibitors could be promising candidates for new anti-microbial agents based on the drug reposition strategy.Sociedade Brasileira de Química2018-02-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersiontext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532018000200297Journal of the Brazilian Chemical Society v.29 n.2 2018reponame:Journal of the Brazilian Chemical Society (Online)instname:Sociedade Brasileira de Química (SBQ)instacron:SBQ10.21577/0103-5053.20170141info:eu-repo/semantics/openAccessWiggers,Helton J.Crusca,EdsonSilva,Éverton E. D.Cheleski,JulianaTorres,Naiara U.Navarro,Marcos V. A. S.eng2018-02-09T00:00:00Zoai:scielo:S0103-50532018000200297Revistahttp://jbcs.sbq.org.brONGhttps://old.scielo.br/oai/scielo-oai.php||office@jbcs.sbq.org.br1678-47900103-5053opendoar:2018-02-09T00:00Journal of the Brazilian Chemical Society (Online) - Sociedade Brasileira de Química (SBQ)false |
dc.title.none.fl_str_mv |
Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases |
title |
Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases |
spellingShingle |
Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases Wiggers,Helton J. c-di-GMP diguanylate cyclase enzymes bacterial biofilm virtual screening drug repositioning |
title_short |
Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases |
title_full |
Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases |
title_fullStr |
Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases |
title_full_unstemmed |
Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases |
title_sort |
Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases |
author |
Wiggers,Helton J. |
author_facet |
Wiggers,Helton J. Crusca,Edson Silva,Éverton E. D. Cheleski,Juliana Torres,Naiara U. Navarro,Marcos V. A. S. |
author_role |
author |
author2 |
Crusca,Edson Silva,Éverton E. D. Cheleski,Juliana Torres,Naiara U. Navarro,Marcos V. A. S. |
author2_role |
author author author author author |
dc.contributor.author.fl_str_mv |
Wiggers,Helton J. Crusca,Edson Silva,Éverton E. D. Cheleski,Juliana Torres,Naiara U. Navarro,Marcos V. A. S. |
dc.subject.por.fl_str_mv |
c-di-GMP diguanylate cyclase enzymes bacterial biofilm virtual screening drug repositioning |
topic |
c-di-GMP diguanylate cyclase enzymes bacterial biofilm virtual screening drug repositioning |
description |
Biofilms are widely present in many human chronic infections, often more resistant to treatment with antibiotics. Bacterial diguanylate cyclases (DGCs) synthesize cyclic dimeric guanosine monophosphate (c-di-GMP) from two guanosine-5'-triphosphate (GTP) molecules. c-di-GMP is a central second messenger controlling biofilm formation, turning this class of enzymes an attractive target to prevent and disrupt biofilms of pathogenic bacteria. Here, we apply an in silico ligand- and target-based hybrid method to screen potential DGC inhibitors from an FDA-approved drug databank. Mass spectrometry assays confirmed that seven screened compounds selectively bound to the GTP active site of P. aeruginosa WspR GGDEF domain. Four out of those, including the anti-inflammatory sulfasalazine and the anti-hypertensive eprosartan, inhibited distinct DGCs (P. aeruginosa WspR and E. coli YdeH) in the micromolar range. Sulfasalazine and eprosartan reduced aggregation in solution of E. coli overexpressing WspR or YdeH. Similar anti-aggregation effects were also observed for sulfasalazine-related anti-inflammatory drugs sulfadiazine and sulfathiazole, the latter a previously described anti-biofilm agent. The optimized pharmacokinetic properties and toxicological profiles of the DGC inhibitors could be promising candidates for new anti-microbial agents based on the drug reposition strategy. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-02-01 |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532018000200297 |
url |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532018000200297 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
10.21577/0103-5053.20170141 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
text/html |
dc.publisher.none.fl_str_mv |
Sociedade Brasileira de Química |
publisher.none.fl_str_mv |
Sociedade Brasileira de Química |
dc.source.none.fl_str_mv |
Journal of the Brazilian Chemical Society v.29 n.2 2018 reponame:Journal of the Brazilian Chemical Society (Online) instname:Sociedade Brasileira de Química (SBQ) instacron:SBQ |
instname_str |
Sociedade Brasileira de Química (SBQ) |
instacron_str |
SBQ |
institution |
SBQ |
reponame_str |
Journal of the Brazilian Chemical Society (Online) |
collection |
Journal of the Brazilian Chemical Society (Online) |
repository.name.fl_str_mv |
Journal of the Brazilian Chemical Society (Online) - Sociedade Brasileira de Química (SBQ) |
repository.mail.fl_str_mv |
||office@jbcs.sbq.org.br |
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1750318180403773440 |