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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 6
[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
Total Affiliations: 2
Document type: Journal article
Source: Journal of the Brazilian Chemical Society; v. 29, n. 2, p. 297-309, FEB 2018.
Web of Science Citations: 1

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)

FAPESP's process: 09/13238-0 - Structural and functional studies of proteins involved in c-di-GMP-mediated signalling pathways
Grantee:Marcos Vicente de Albuquerque Salles Navarro
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 10/19109-4 - Design of Diguanilate Cyclase Inhibitors Involved in the Formation of Bacterial Biofilms
Grantee:Helton José Wiggers
Support type: Scholarships in Brazil - Post-Doctorate