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| Author(s): |
Paulo Vinicius da Mata Madeira
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2019-02-14 |
| Examining board members: |
Andréa Dessen;
Paulo Henrique Conaggin Godoi;
Ana Carolina de Mattos Zeri;
Gustavo Fernando Mercaldi;
Juliana Ferreira de Oliveira
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| Advisor: | Andréa Dessen |
| Abstract | |
According to the World Health Organization infectious diseases are the second leading cause of death worldwide. The peptidoglycan is an important structure present in the cell wall of almost all eubacteria, and its role is to confer rigidity and shape. In addition, it is also important in processes such as division, growth and protection from osmotic lysis. Thus the peptidoglycan is 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 consists of 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 TP (Transpeptidase) domain of PBPs, inhibiting the activity of these proteins which catalyze an essential step of peptidoglycan synthesis. Due to their successful bacteriolytic activity, beta-lactam compounds have been used for over 60 years. Bacteria can overcome the action of antibiotics in different ways; for example, it is now known that 25% of all invasive strains of S. pneumoniae are penicillin-resistant, mainly due to structural changes in the transpeptidase (TP) domain of PBPs that prevent binding of antibacterial compounds. Thus, searches for novel compounds that can use this same important mechanism of inhibition have been encouraged worldwide. Natural extracts show great chemical diversity, including new compounds, and could serve as prototypes for the development of new drugs. Thus, this pioneer study aims to use commercial libraries as well as newly assembled ones with novel natural compounds for testing in High Throughput Screening at the Brazilian Biosciences National Laboratory (LNBio). In addition, orthogonal assays and X-ray crystallography experiments were also performed in the search for new molecules able to bind to the TP domain and that could eventually be used as starting points for rational design of new antibacterial agents. A compound was identified and isolated from an ethanolic fraction of natural product and was shown to be capable of interacting with PBP2x by fluorescence anisotropy assay and Nuclear Magnetic Resonance, thus being the first non-covalent inhibitor reported for that essential bacterial target (AU) | |
| FAPESP's process: | 14/11980-9 - Identification and structural characterization of new compounds for PBPs inhibition |
| Grantee: | Paulo Vinicius da Mata Madeira |
| Support Opportunities: | Scholarships in Brazil - Doctorate |