Identification and development of new molecules against Mycobacterium tuberculosis based inhibition of protein metabolism of sulfur -Based methodology using fragments

• Grant number: 14/20921-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: February 01, 2015
• End date: May 31, 2019
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Andrea Balan Fernandes
• Grantee: Andreia Navarro Cerone
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Mycobacterium tuberculosis is the bacterium that causes tuberculosis, a disease that causes 2 million deaths a year and infects about one third of the world population. The treatment of tuberculosis patients is time consuming and based on a cocktail of drugs that have led to the development of multiresistant strains. This project aims to identify new drugs that can be used to inhibit the microorganism more efficiently and quickly. For this we focus on protein metabolism of sulfur, a key metabolic pathway for the bacteria, whose importance for infection and pathogenesis has been demonstrated functionally, and in the development of drugs based on fragments methodology, considered the most direct and modern way to identify new molecules of medical and pharmaceutical interest. The main targets of this work are two proteins: Subi - binding of sulfate and PAPS reductase - CysH. These proteins were intentionally chosen for locating in different regions of the cell: the cytoplasm and periplasm, respectively, for presenting forms of interaction with its ligands / substrates and perform different functions at different stages of the pathway. The proteins are expressed and purified for interaction with different drugs, tests and validation tests once identified one or more molecules of interest, their structures will be resolved in the presence of the same for the development of drugs based on fragments. For a complete understanding of the pathway of sulfate uptake and assimilation are also characterized the cyst, CysW, CysA1, CysA2, CysD, CysN, Nira, CysK1, CysK2 and CysM proteins. (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)

MEZA, A. N.; CAMBUI, C. C. N.; MORENO, A. C. R.; FESSEL, M. R.; BALAN, A.. Mycobacterium tuberculosis CysA2 is a dual sulfurtransferase with activity against thiosulfate and 3-mercaptopyruvate and interacts with mammalian cells. SCIENTIFIC REPORTS, v. 9, NOV 14 2019. (14/20921-6, 15/14514-1, 16/03196-1, 18/20162-9)

Academic Publications

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

CERONE, Andreia Navarro. Characterization of the sulfate capture/assimilation pathway in Mycobacterium tuberculosis: strategies for the development of inhibitors and potential vaccinal and diagnosis targets. 2019. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.