Project 2: Isolation Chemistry of Cultured Cyanobacteria

Ohio State University, Columbus OH

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Abstract

PROJECT SUMMARY – PROJECT 2 The overarching goal of this Program Project Grant renewal application is to discover natural products that can serve as anticancer drug leads from diverse natural sources. Project 2, located at the College of Pharmacy, University of Illinois at Chicago (UIC), is comprised of microbial, chemical and biological elements. The primary goals for Project 2 are the discovery of new lead anticancer compounds from cyanobacteria. The underlying hypothesis for Project 2 is that the diverse natural product structures from cultured non-marine cyanobacteria will be a rich source for anticancer leads. To achieve the stated goals the Specific Aims for Project 2 are as follows: 1) to obtain, culture, extract, and prepare fractions of cyanobacterial strains, and to sequence the genome of selected strains. We will obtain 100 cyanobacterial strains per year. The strain collection will focus on samples collected in the Upper Midwest and Great Lakes regions of the U.S. Each strain will be cultured, extracted, fractionated, and provided for biological evaluation in the biological test systems available at Core 1 (UIC) and Project 1 (OSU) and Project 3 (UNCG). 2) To isolate and determine the structures of active cyanobacterial metabolites, and to improve yields of lead compounds. Extracts showing promising activity will be fractionated using activity-monitored fractionation to obtain pure natural product(s). The structurally characterized, active isolates will be extensively evaluated in the biological test systems available to the program. We will re-isolate larger amounts of any candidate compound. To improve yields, when necessary, we will evaluate different cultivation conditions. 3) To explore biosynthetic potential of our cyanobacterial library. Our cyanobacterial strain library currently contains close to 1500 isolates and represents one of the largest collections in the U.S. As a complementary and integrated approach aimed at increasing the structural diversity of our compound library, we will sequence the genomes of ~100 strains. Strains will be selected for sequencing based on promising biological activity and/or taxonomic diversity. For a subset of strains (~10), we will also attempt to activate potentially silent pathways by cultivating the strains under different culture conditions. The various interactions and information exchanges envisioned among the components of this Program Project will greatly enhance our chances of achieving our collective goal of finding useful, naturally occurring cancer chemotherapeutic leads.