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Design of diguanilate cyclase inhibitors involved in the formation of bacterial biofilms

Grant number: 10/19109-4
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): July 01, 2011
Effective date (End): July 02, 2015
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Marcos Vicente de Albuquerque Salles Navarro
Grantee:Helton José Wiggers
Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated research grant:09/13238-0 - Structural and functional studies of proteins involved in c-di-GMP-mediated signalling pathways , AP.JP
Associated scholarship(s):13/23163-2 - Fragment-based screening for inhibitors of bacterial enzymes diguanylate and diadenylate cyclases using X-ray crystallography, BE.EP.PD

Abstract

Depending on the environmental stimuli, bacteria that normally live in a planktonic form adhere to a surface, forming cellular communities called biofilms. Despite the complexity and the involvement of several bacterial systems, it is known that the intracellular level of a small signaling molecule (c-di-GMP) controls this phenotypic transition. High concentrations of c-di-GMP usually implies in biofilms formation. Bacterial communities are highly resistant to conventional treatment with antibiotics and represent the predominant phenotype in most chronic infections, resulting in serious medical problems. The c-di-GMP is synthesized from two GTP molecules by enzymes diguanilate cyclases (DGC) belonging to GGDEF family, which are, therefore, potential targets for developing new therapies that interfere with the process of biofilm formation. In this project, we propose the application of computational methods for identifying ligands of enzymes diguanilate cyclases, evaluate the molecular recognition of compounds identified by kinetic methods, thermodynamic and structural characterization. For this, two already characterized DGC (WSPR from Pseudomonas aeruginosa and YdeH from Escherichia coli) and two enzymes not studied yet from Xantomonas axonopodis (XAC2482 and XAC0614) will be cloned and tested for kinetic and structural studies with the identified inhibitors. It is expected that analysis of interactions between selected compounds and DGCS provide the basis for the development of specific inhibitors of this enzyme family and allow understanding the molecular mechanisms involved in signaling by c-di-GMP.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
WIGGERS, HELTON J.; CRUSCA, EDSON; SILVA, EVERTON E. D.; CHELESKI, JULIANA; TORRES, NAIARA U.; NAVARRO, MARCOS V. A. S. Identification of Anti-Inflammatory and Anti- Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases. Journal of the Brazilian Chemical Society, v. 29, n. 2, p. 297-309, FEB 2018. Web of Science Citations: 1.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.