Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases

Detalhes bibliográficos
Autor(a) principal: Wiggers,Helton J.
Data de Publicação: 2018
Outros Autores: Crusca,Edson, Silva,Éverton E. D., Cheleski,Juliana, Torres,Naiara U., Navarro,Marcos V. A. S.
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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spelling 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
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dc.identifier.uri.fl_str_mv http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532018000200297
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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
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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)
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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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