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Identification of new antibacterial agents in libraries of natural products

Grant number: 15/19906-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2016
Effective date (End): February 29, 2020
Field of knowledge:Biological Sciences - Biochemistry - Biochemistry of Microorganisms
Principal Investigator:Andrea Dessen de Souza e Silva
Grantee:Fernanda Rodrigues da Costa
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil
Associated research grant:17/12436-9 - ANTIBIO-BAC: exploring the bacterial cell wall as a target for novel antibiotherapies, AP.SPEC
Associated scholarship(s):18/07148-7 - New antibiotic development through exploration of the bacterial cell wall formation machinery, BE.EP.DR

Abstract

ABSTRACT Introduction: Antimicrobial resistance is a serious public health problem. Infections caused by bacteria that are resistant to several classes of antimicrobials are an increasingly common fact in the nosocomial environment. Once the therapeutic options have become inactive due to resistance issues, hospital therapies can be limited to antimicrobials that are often more toxic and less effective. Thus, this study aims at screening libraries of novel natural products containing a high percentage of biodiversity samples from Brazil and Antarctica, which available at the Laboratório Nacional de Biociências (LNBio- CNPEM) against a Gram-negative and a Gram-positive bacterial cell line in order to identify new compounds inhibit or totally block bacterial growth. Justification: Pathogenic bacteria suffer an intense selective pressure caused by the constant use of antibiotics and antiseptic compounds, resulting in the spread of resistance markers in the hospital environment, and consequently multidrug resistance. Unfortunately it happens faster than the introduction of new antimicrobial agents in clinics. For this reason, the landscape of antimicrobial resistance worldwide is threatening, especially in Latin America which accounts for a wide range of pathogens displaying different resistance mechanisms. This fact, combined with the low perspective of introduction of new therapeutic options by pharmaceutical companies, underlines the importance of undertaking studies aimed at discovering novel compounds with antibiotic action. This research project is one of the first efforts to identify potential new antibiotics from natural product libraries of the Brazilian biodiversity. Materials and Methods: Initially, we will screen four different types of natural product libraries which are available in the Chemical Laboratory of Natural Products (LQPN-LNBio), with the purpose of identifying novel compounds with antibiotic action. We will employ two non-pathogenic laboratory strains (Escherichia coli K12 and Streptococcus pneumoniae R6). The initial tests will be made on solid and liquid bacterial growth media, and the best method will be chosen for the library screening steps (which represents approximately 10,000 compounds). The most promising compounds that are able to inhibit or completely prevent the growth of such strains will be characterized. We will determine the minimum inhibitory concentration (MICs) for each compound using laboratory and pathogenic strains, the latter in collaboration with the laboratory of Professor Bernard Joris at the University of Liege in Belgium. Since the libraries contain both extracts and purified compounds, if our 'hits' are extract samples we will perform their re-fragmentation in collaboration with the group of Dr. Daniela Trivella, in order to identify active substances. One major, and exciting, challenge in the project will be to identify the biochemical pathway that is inhibited/affected by our hits. The scientific and technological environment of the LNBio is optimal for the development of this challenging and novel project. (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)
RODRIGUES-COSTA, FERNANDA; SLIVINSKI, JULIANO; IOCA, LAURA P.; BERTONHA, ARIANE F.; DE FELICIO, RAFAEL; DA CUNHA, MARCOS GUILHERME; DA MATA MADEIRA, PAULO VINICIUS; CAUZ, ANA C. G.; TRINDADE, DANIEL MARAGNO; FREIRE, VITOR F.; ROPKE, CRISTINA DISLICH; GALES, ANA; BROCCHI, MARCELO; FERREIRA, ANTONIO G.; GUEIROS-FILHO, FREDERICO; BARBOSA TRIVELLA, DANIELA BARRETTO; BERLINCK, ROBERTO G. S.; DESSEN, ANDREA. Merulinic acid C overcomes gentamicin resistance in Enterococcus faecium. BIOORGANIC CHEMISTRY, v. 100, JUL 2020. Web of Science Citations: 0.

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