Busca avançada
Ano de início
Entree
(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

Texto completo
Autor(es):
Wiggers, Helton J. [1, 2] ; Crusca, Edson [1] ; Silva, Everton E. D. [1] ; Cheleski, Juliana [1, 2] ; Torres, Naiara U. [1] ; Navarro, Marcos V. A. S. [1]
Número total de Autores: 6
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Fis, Dept Fis & Ciencia Interdisciplinar, BR-13566590 Sao Carlos, SP - Brazil
[2] Univ Oeste Parana UNIOESTE, CECE, BR-85903000 Toledo, PR - Brazil
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: Journal of the Brazilian Chemical Society; v. 29, n. 2, p. 297-309, FEB 2018.
Citações Web of Science: 1
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. (AU)

Processo FAPESP: 10/19109-4 - Planejamento de Inibidores de Diguanilato Ciclases Envolvidas na Formação de Biofilmes Bacterianos
Beneficiário:Helton José Wiggers
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 09/13238-0 - Estudos estruturais e funcionais de proteínas envolvidas em vias de sinalização celular mediadas por c-di-GMP
Beneficiário:Marcos Vicente de Albuquerque Salles Navarro
Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores