Integrated strategies for natural product discovery from Brazilian cyanobacteria

Abstract

Natural products continue to provide important chemical scaffolds for the development of pharmaceutical drugs. Prospecting understudied organisms and utilizing orthogonal approaches are strategies that can be integrated to improve natural product discovery. Cyanobacteria are photosynthetic prokaryotes known to produce secondary metabolites with biological activity. Nonetheless, the chemistry of cyanobacteria remains understudied. Our research group has implemented a pipeline for creating a library of prefractionated extracts from cultured cyanobacteria. Biological assays along with metabolomics have been employed for analyzing and prioritizing samples for follow up investigations. In this project, we propose to extend this pipeline towards systematizing dereplication and achieving the isolation and elucidation of novel natural products from Brazilian cyanobacteria. We will also diversify prospection approaches aiming at augmenting the chances of discovery. Prefractionated extracts will be subjected to a secondary HPLC fractionation followed by microscale dereplication using mass spectrometry and nuclear magnetic resonance spectroscopy. An additional dereplication strategy will combine stable isotope labeling and metabolomics. Complementary prospection strategies based on genome mining and elicitor screening will be applied. Novel and bioactive molecules will be prioritized for isolation and structure elucidation. This project aims at establishing a line of research in microbial natural product discovery at the School of Pharmaceutical Sciences (USP). It will create research opportunities for undergraduate, masters, and Ph.D. students. We also propose to update the scope of a graduate-level course and an undergraduate course, as well as to develop a collaborative textbook addressing topics related to the current project. (AU)