Identification and structural characterization of new compounds for PBPs inhibition

• Grant number: 14/11980-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2014
• End date: March 31, 2018
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Andrea Dessen de Souza e Silva
• Grantee: Paulo Vinicius da Mata Madeira
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated research grant: 11/52067-6 - Assembly and structure of macromolecular complexes involved in bacterial cell wall: biosynthesis and virulence, AP.SPEC

Abstract

According to the World Health Organization infectious diseases are the second leading cause of death worldwide. These diseases are caused by pathogenic microorganisms that shows specific mechanisms in order to increase the success of the infective process and survival in the host environment. Historically bacterial pathogens have been combated through the successfully use of antibiotics that inhibit metabolic pathways or vital processes to their survival and bacterial replication. The peptidoglycan, an important structure present in the cell wall of almost all eubacteria and confers rigidity and shape to these bacteria as well as being important in processes such as division, growth and osmotic lysis protection. Thus the peptidoglycan presents itself as an important antibacterial target and the inhibition of its synthesis is the target of a large class of antibiotics used for decades with great success. The main group of this class are the beta-lactam compounds such as penicillin that due to structural similarity to the natural substrate of PBPs (Penicillin Binding Proteins) are able to bind to the active site of these proteins. The mechanism of inhibition occurs through covalent binding between the beta-lactam ring and the conserved domain PB (Penicillin Binding) of PBPs, inhibiting the activity of these proteins that catalyzes an essential step of peptidoglycan synthesis. Due to the successful bactericide activity, beta-lactam compounds such as penicillin , have been used for over 60 years. The bacteria can overcome the action of antibiotics in different ways, it is now known that 25% of all invasive strains of S. pneumoniae are penicillin resistant, mainly due to structural changes in the PB domain of PBPs that prevents the binding of antibacterial compounds. Thus, searches for novel compounds that can use this same important mechanism of inhibition has been encouraged worldwide. Natural extracts shows a great chemical diversity, including new compounds, serving as prototypes for the development of new drugs. Thus, this study aims to use some commercial libraries as well as newly assembled ones with novel natural compounds for testing in High Throughput Screening at the National Laboratory for Biosciences (LNBio) in order to identify new compounds that can binds the PB domain and could be used as a starting point for the rational design of new drugs since it will also be performed the structural determination of PBP in the presence of the ligand by X-ray crystallography. (AU)

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)

DA MATA MADEIRA, PAULO VINICIUS; ZOUHIR, SAMIRA; BASSO, PAULINE; NEVES, DAVID; LAUBIER, AURELIE; SALACHA, RICHARD; BLEVES, SOPHIE; FAUDRY, ERIC; CONTRERAS-MARTEL, CARLOS; DESSEN, ANDREA. Structural Basis of Lipid Targeting and Destruction by the Type V Secretion System of Pseudomonas aeruginosa. Journal of Molecular Biology, v. 428, n. 9, p. 14-pg., 2016-05-08. (11/52067-6, 14/11980-9, 13/01962-0)

DA MATA MADEIRA, PAULO VINICIUS; ZOUHIR, SAMIRA; BASSO, PAULINE; NEVES, DAVID; LAUBIER, AURELIE; SALACHA, RICHARD; BLEVES, SOPHIE; FAUDRY, ERIC; CONTRERAS-MARTEL, CARLOS; DESSEN, ANDREA. Structural Basis of Lipid Targeting and Destruction by the Type V Secretion System of Pseudomonas aeruginosa. Journal of Molecular Biology, v. 428, n. 9, A, p. 1790-1803, MAY 8 2016. (11/52067-6, 13/01962-0, 14/11980-9)

RODRIGUES-COSTA, FERNANDA; SLIVINSKI, JULIANO; IOCA, LAURA P.; BERTONHA, ARIANE F.; DE FELICIO, RAFAEL; DA CUNHA, MARCOS GUILHERME; DA MATA MADEIRA, PAULO VINICIUS; CAUZ, ANA C. G.; TRINDADE, DANIEL MARAGNO; FREIRE, VITOR F.; et al. Merulinic acid C overcomes gentamicin resistance in Enterococcus faecium. BIOORGANIC CHEMISTRY, v. 100, JUL 2020. (16/05133-7, 13/50228-8, 11/52067-6, 17/12436-9, 15/19906-5, 14/11980-9)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

MADEIRA, Paulo Vinicius da Mata. Identification and structural characterization of new PBPs inhibitors. 2019. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.