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Studies with B.subtilis stringent response and search for small molecules capable of modulating RelA protein

Grant number: 14/26528-4
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): February 01, 2016
Effective date (End): August 31, 2017
Field of knowledge:Biological Sciences - Biochemistry - Biochemistry of Microorganisms
Principal Investigator:Frederico José Gueiros Filho
Grantee:André Arashiro Pulschen
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Living on the environment, within a host or other habitats, bacteria are often facing adverse conditions such as exposure to antibacterial compounds or nutritional deficiency. In situations like this, bacteria cells are capable of activating the stringent response, which is modulated by the alormone (p)ppGpp. Classically, the stringent response were described as an bacterial adaptation to lack of amino acids, adjusting the metabolism for maintaining cells viability. The amino acid deficiency increases the intracellular levels of (p)ppGpp, which promotes the inhibition of rRNA, tRNA and transcriptional process, at the same time that it activates amino acids biosynthesis operons. It is also known that the stringent response has a correlation with others important nutritional deficiencies in E.coli, as for example the lack of fatty acids. However, it is not known if the same process occurs on B.subtilis or other gram-positive bacteria. The intracellular (p)ppGpp levels are regulated by enzymes from RelA/SpoT family, responsible for synthesizing and hydrolyzing this secondary messenger. By the years, it has been discovered that (p)ppGpp acts directly and indirectly affecting many cellular processes such as, motility, antibiotic resistance, among others, in order to tailor the bacterial metabolism to changes in the environment, which demonstrate that (p)ppGpp acts as an central regulator, that connects metabolic information with adaptive responses. With that in mind, the stringent response has become a potential target for the development of drugs capable of sensitizing pathogenic strains to antibiotics, diminish virulence and persistence of microorganisms. Molecules that are capable of lowering internal levels of (p)ppGpp could constitute new weapons for fighting the increasing problem of antimicrobial resistance. Therefore, the present work has as one of its objectives searching in a chemical library of 12000 different compounds molecules capable of directly interacting with B.subtilis RelA protein, preventing the synthesis or increasing the hydrolysis of (p)ppGpp. Another important objective of this work is to study is to study the correlation between stringent response of B.subtilis and lack of fatty acids, and how (p)ppGpp contributes to maintaining the viability of the cells in such conditions. Also, the investigation will include the investigation of the signal pathway that connects the lack of fatty acids and the RelA enzyme activation. (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)
PULSCHEN, ANDRE A.; SASTRE, DIEGO E.; MACHINANDIARENA, FEDERICO; ASIS, AGOSTINA CROTTA; ALBANESI, DANIELA; DE MENDOZA, DIEGO; GUEIROS-FILHO, FREDERICO J.. The stringent response plays a key role in Bacillus subtilis survival of fatty acid starvation. Molecular Microbiology, v. 103, n. 4, p. 698-712, . (14/26528-4, 14/13411-1)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
PULSCHEN, André Arashiro. Studies of the stringent response of Bacillus subtilis and search for small molecules capable of modulating RelA activity. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.

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