Biosynthetic studies of bioactive macrolactone polyketide from Streptomyces sp. ICBG311

• Grant number: 19/16559-3
• Support type: Scholarships in Brazil - Master
• Effective date (Start): November 01, 2019
• Effective date (End): July 31, 2021
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal researcher: Mônica Tallarico Pupo
• Grantee: Vitor Bruno Lourenzon
• Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/50954-0 - Novel therapeutic agents from the bacterial symbionts of Brazilian invertebrates, AP.BTA.TEM

Abstract

Natural products play an important role in the discovery of new bioactive compounds, inspiring the development of new drugs. In this context, the microorganisms have a remarkable contribution since they are capable of produce several active secondary metabolites against different pathogens. For this reason, the association with microorganisms proved to be an important evolutionary advantage for the most diverse living beings such as plants, insects, and animals, which can use these compounds to protect themselves against parasites. A well-known example of this type of symbiosis is the association of Attine ants with the actinobacteria that produce active compounds against specific parasites of the fungus cultivated by the ants as a source of nutrients. Recent studies carried out at the Laboratory of microbial chemistry (LQMo - FCFRP) have been identified from the cultivation of actinobacteria Streptomyces sp. ICBG311, isolated from winged males of Cyphomyrmex fungus-growing ants, three structurally related polyketides, two of them new: ciphomycin and epoxycomycin and one already described in the literature: GT-35. The compounds showed great antifungal potential being active against different strains of the entomopathogenic fungus Escovopsis and also against human pathogens Candida albicans K1, C. glabrata 4720 (triazole resistant), C. auris B11211 (echinocandin, triazole, and amphotericin resistant strains). B) and Aspergillus fumigatus 11628 (echinocandin resistant), besides high antiparasitic activity against the intracellular amastigote and promastigote forms of Leishmania donovani. Thus, the present project aims to elucidate the biosynthetic pathway of ciphomycin and the analogs, by combining the technique of incorporation isotopically labeled 13C precursors and in silico analysis of the complete lineage genome for cluster identification and analysis of biosynthetic genes responsible for the production of the compounds. The determination of the biosynthetic pathway of structurally complex compounds with promising pharmacological potential is important to enabling further studies of microbial genetic manipulation to obtain simplified analogs, structure-activity studies and to obtain safer and more efficient derivatives. (AU)