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UF Health University of Florida
Department of Medicinal Chemistry College of Pharmacy
Research Overview

Collaborative Program Grant for Multidisciplinary Teams (RM1)

The NIGMS Collaborative Program Grant for Multidisciplinary Teams (RM1) funds highly integrated team research by investigators addressing a single-focused, ambitious, and challenging project that cannot be addressed by individual R01 applications. Groups are typically ​​comprised of three to six principal investigators with a topic central to the NIGMS mission areas ​where projects cannot be achieved by individual efforts. The RM1 program requires the participation of multiple investigators with complementary expertise to achieve the team’s research objectives and with well-defined goals that can be achieved within 5-10 years. The “Integrative Multidisciplinary Discovery Platform to Unlock Marine Natural Product Therapeutic Opportunities” grant was awarded to principal investigator Hendrik Luesch, Ph.D., and co-principal investigators Yousong Ding, Ph.D., and Steven Bruner, Ph.D., from UF, as well as Mohamed Donia, Ph.D., from Princeton University and Valerie Paul, Ph.D., from the Smithsonian Marine Station.

The genomes of cyanobacteria and sponge-associated microbes encode numerous compounds that could provide the basis for new drugs. Discovery and development of these chemicals as drug candidates, however, is challenging due to their low availability in Nature. The proposed multidisciplinary research will address this limitation and should provide the methodology to increase the number of new natural products as starting points for drug discovery and development.

Project Summary

We have assembled an entirely Florida-centric collaborative research team with collective expertise in microbial natural products chemistry and pharmacology, genomics, bacterial enzymology, bioinformatics, synthetic biology, chemical synthesis, and cyanobacterial and sponge chemical ecology and phylogenetics. The team is complemented by an out-of-state expert in metagenomics and bioinformatics integration. This geographical cluster of expertise being in the state with the greatest marine biodiversity in the continental US provides a dual benefit and unique opportunity to explore systems that are likely to hold some of the most promise in terms of biosynthetic potential: marine cyanobacterial communities, consisting of benthic filamentous cyanobacteria that are associated with unique microbial diversity, and sponges and their associated rich and unique microbiome in a local hotspot of biodiversity. Compounds produced by these communities are known to cover therapeutically relevant chemical space and are therefore suited as starting points for drug discovery. In a targeted fashion, we will obtain high quality (meta)genome and (meta)transcriptome sequence information from sponge-associated microbiomes and cyanobacteria using state-of-the-art sequencing techniques. We will build an integrated, multi- component platform that leverages existing bioinformatics tools and newly developed artificial intelligence-based tools to shine new light at their genomes with the goal of identifying novel biosynthetic gene clusters, particularly those unattainable with current tools, and even chemical skeletons. We will express natural products encoded by the clusters by employing five types of complementary synthetic biology systems that we have strategically developed over the past several years. These systems originating from five bacterial phyla commonly associated with both marine cyanobacterial and sponge samples cover diverse genetic backgrounds and are expected to effectively translate the identified genetic information of a variety of organisms into chemicals with proper system optimization. We will evaluate and analyze metabolites and expression profiles using LC-MS-based metabolomics and NMR and characterize associated new enzymology. Natural products derived from chemical extract and fraction libraries and those generated through our expression systems or chemical synthesis will be tested in our multidimensional screening platform, consisting of unbiased phenotypic assays in various in vitro and in vivo models as well as experimental and computational target-based functional assays. This approach will enable us to capture a broad array of activities from expressed and unexpressed genes. Selected bioactive natural products will be scaled by chemical synthesis, and bioprobes and enzyme substrates will be prepared for in-depth biological studies and enzymology research, respectively. Successful completion of these aims by our established multidisciplinary investigator team should deliver promising therapeutically important drug leads and tool compounds through thoroughly exploring marine organisms while addressing the current major limitations of natural products drug discovery over the next ten years.

Research Team

Principal Investigators (Steering Committee)

Hendrik Luesch

University of Florida

Hendrik Luesch, Ph.D.

Dr. Ding

University of Florida

Yousong Ding, Ph.D.

Steve Bruner

University of Florida

Steve Bruner, Ph.D.

Valerie Paul

SMITHSONIAN MARINE STATION

Valerie Paul, Ph.D.

Mohamed Donia

Princeton University

Mohamed Donia, Ph.D.

Co-Investigators and Collaborators

External Advisory Committee

Scientific Project Manager

Publications