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Structural investigation of ramnose synthesis and implications in antibiotic resistance

Grant number: 20/03983-9
Support type:Regular Research Grants
Duration: December 01, 2020 - November 30, 2022
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal researcher:Alessandro Silva Nascimento
Grantee:Alessandro Silva Nascimento
Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

It is estimated that 700,000 deaths are caused directly annually by bacterial infections resistant to antibiotics. The increasing levels of antibiotic resistance available have led the United States Center for Disease Control and Prevention (CDC) to establish four broad lines of action to address the problem of resistance: the prevention of infections and the spread of resistance, screening resistant bacteria, improved use of current antibiotics and the development of new antibiotics. Most of these actions, in the academic context, require a deeper knowledge of resistance acquisition mechanisms and the identification of potential targets for the development of new antibiotics. One class of enzymes that has been shown to be directly involved in resistance development processes is that of enzymes involved in the decoration of the bacterial cell wall. Recent data in the scientific literature clearly demonstrate that wall decoration is directly related to resistance to beta-lactam antibiotics, through mechanisms still little known. Thus, the deletion of some enzymes was shown to be able to reduce the minimum inhibitory concentration of beta-lactams for S. aureus (MRSA) and E. faecalis. In this project, we propose the heterologous expression of enzymes involved in the synthesis of rhamnose aiming at its structural, biophysical and biochemical characterization. This saccharide is used by several pathogenic bacteria such as Streptococcus, Pseudomonas aeruginosa, Enterococcus spp, among others for the composition of the polysaccharide capsule that decorates the peptidoglycan. In some cases, as in Mycobacterium tuberculosis, for example, enzymes are essential. In other cases, as in P. aeruginosa, enzymes are important for virulence. At the end of the project we hope to be able to determine crystallographic structures of the enzymes involved in the synthesis of rhamnosis, in addition to understanding their interaction with substrate and allosteric regulators. We also aim to characterize the hydrodynamic behavior of enzymes and to evaluate the screening of compounds as potential inhibitors that allow a deeper assessment of the role of enzymes in vitro. (AU)

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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)
BARRA, ANGELICA LUANA C.; ULLAH, NAJEEB; MORAO, LUANA G.; WRENGER, CARSTEN; BETZEL, CHRISTIAN; NASCIMENTO, ALESSANDRO S.. Structural Dynamics and Perspectives of Vitamin B6 Biosynthesis Enzymes in Plasmodium: Advances and Open Questions. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, . (18/21213-6, 19/20219-3, 20/03983-9, 15/13684-0, 19/26428-3, 15/26722-8, 17/03966-4)
BRIGANTI, LORENZO; CAPETTI, CAIO; PELLEGRINI, VANESSA O. A.; GHIO, SILVINA; CAMPOS, ELEONORA; NASCIMENTO, ALESSANDRO S.; POLIKARPOV, IGOR. Structural and molecular dynamics investigations of ligand stabilization via secondary binding site interactions in Paenibacillus xylanivorans GH11 xylanase. COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL, v. 19, p. 1557-1566, . (15/13684-0, 15/26722-8, 20/03983-9)
DE PAULA, KARINA; SANTOS, JADEMILSON C.; MAFUD, ANA CAROLINA; NASCIMENTO, ALESSANDRO S.. Tetrazoles as PPAR gamma ligands: A structural and computational investigation. JOURNAL OF MOLECULAR GRAPHICS & MODELLING, v. 106, . (10/15376-8, 20/03983-9, 14/06565-2, 15/26722-8)

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