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Chemical study and strategies for modifying the secondary metabolism of endophytic actinobacteria

Grant number: 11/11703-7
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): September 01, 2011
Effective date (End): January 31, 2015
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Mônica Tallarico Pupo
Grantee:Larissa Varella Bacha
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Microorganisms are prolific producers of bioactive natural products. Several clinically important drugs have microbial origin, and most of the therapeutically used antibiotics are produced by actinobacteria, mainly from the genus Streptomyces. The multidrug resistance observed in pathogenic microorganisms and tumor cells lead to the need for new antibacterial and antitumor drugs. Endophytic actinobacteria have shown great potential in the search for bioactive natural products. This work describes the chemical study of two endophytic actinobacteria strains: Streptomyces sp. RTd 22 and Streptomyces sp RTD 31, isolated from Tithonia diversifolia roots. Active fractions in biological assays were further fractionated for identifying the bioactive compounds, which are: the macrolide antibiotics concanamycins (S31-1) and B (S31-2), anhydrous aglycones of concanamycins A (S31-3) and B (S31-4), all four produced by Streptomyces sp. RTd31, and the ionophore polyether grisorixin (S22-2), produced by Streptomyces sp. RTd22. The production of these bioactive compounds was monitored by UPLC-MS via the SIM mode. Concanamycins A and B had maximum production at 96 h, and grisorixin at 192 h. Other compounds identified by the dereplication of buthanolic extracts of both actinobacteria were the siderophore norcardamine (S31-7) and deoxy-nocardamine (S31-8), the siderophores desferrioxamine B (S31-9) was identified only in buthanolic extracts of Streptomyces sp RTd31. Experiments varying media and co-culture were tested to stimulate the biosynthesis of novel compounds, but nothing new was identified. By genome sequencing of Streptomyces sp RTd22 and antiSMASH analysis it was possible to verify the presence of several biosynthetic clusters in the genome of this strain. It was possible to identify the biosynthetic clusters of himastatin (S22-4) and its analogous compound coelichelin (S22-5); however, these compounds were not biosynthesized in the culture conditions used. The grisorixin biosynthetic cluster was determined, and homologous recombination was performed for deleting the analogue gene of nigericin flavin monooxygenase nigCI. Two mutants were obtained, and one of them was cultured for analyzing its metabolic profile. There was no production of grisorixin, but the cyclic ionophores nonactin (S22-6) monactin (S22-7), dynactin (S22-8), trinactin (S22-9) and tetranactin (S22-10) were produced and detected by mass spectrometry. (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)
CHAGAS, FERNANDA O.; RUZZINI, ANTONIO C.; BACHA, V, LARISSA; SAMBORSKYY, MARKYIAN; CONTI, RAPHAEL; PESSOTTI, RITA C.; DE OLIVEIRA, LUCIANA G.; CLARDY, JON; PUPO, MONICA T.. Genome Sequence of Streptomyces sp. Strain RTd22, an Endophyte of the Mexican Sunflower. MICROBIOLOGY RESOURCE ANNOUNCEMENTS, v. 4, n. 4, . (13/07600-3, 08/09540-0, 13/50954-0, 09/17695-6, 08/00812-7, 11/06209-3, 11/12910-6, 11/11703-7)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
BACHA, Larissa Varella. Chemical study and strategies for modifying the secondary metabolism of endophytic actinobacteria. 2015. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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