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Study of the direct interactions, crystallization and structure of the binary complexes between Mur enzymes from Streptococcus pneumoniae

Grant number: 18/16346-7
Support type:Scholarships in Brazil - Master
Effective date (Start): December 01, 2018
Effective date (End): July 31, 2020
Field of knowledge:Biological Sciences - Genetics
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Andrea Dessen de Souza e Silva
Grantee:Karina Tamie Shirakawa
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil

Abstract

The peptidoglycan is an essential component of the cell wall of Gram-positive and Gram-negative bacteria, and its absence or deficiency can lead to cell death making it an excellent target for the development of new antibiotics. However, due to the increasing antibiotic resistence by many microorganisms, the search for new molecular and antimicrobial targets has resurfaced, directing the studies to other steps and enzymes involved in peptidoglycan biosynthesis. The initial steps of this biosynthesis are performed in the cytoplasm by Mur enzymes, forming UDP-MurNAc-pentapeptide. Many inhibitors have been characterized in vitro for these enzymes. Although lack of evidence of its functionality in vivo raises the hypothesis that these inhibitors do not have access to the active site of the enzymes in the bacterial cytoplasm due to the possible formation of a megaprotein complex whose structure would block the catalytic sites. Further studies reinforce this hypothesis, demonstrating that Mur enzymes are capable of forming oligomers and of interacting with other Mur enzymes, forming binary complexes. Thus, this Master project aims to continue the characterization of Mur enzymes from Streptococcus pneumoniae, especially the direct interactions, crystallization and structure resolution of the binary complex between MurC and MurD (ATP-dependent Mur ligases), and, if possible, MurG. The results will provide more information for a better understanding of the bacterial peptidoglycan formation process, which may be useful for the eventual development of new antibiotics targeting this pathway.