# Development of an efficient cyanobacterial platform for heterologous expression and biosynthetic interrogations of natural products.

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $291,678

## Abstract

Project Summary
This project will overcome a main obstacle impeding progress to fully exploit marine natural products (NPs) for
health applications. Currently, there are no efficient genetic methods to interrogate and modify endogenous NP
biosynthetic pathways from marine filamentous cyanobacteria, and no robust platforms for heterologous
expression and genetic engineering of cyanobacterial NP pathways. This project will develop methods and tools
for engineering cyanobacteria for the heterologous expression and manipulation of NP gene clusters identified
in organisms that are not amenable to genetic methods, or orphan NP gene clusters that are identified in
environmental DNA sequences. The project will use the synthetic-biology strain Synechococcus elongatus
PCC7942 and the marine filamentous cyanobacterium Leptolyngbya (ISB-3N94-8PLP) to provide two distinct
but complementary genetic platforms for the expression and engineering of NP pathways. The long-term
objectives of this project are to provide efficient platforms for the production of NPs in quantities suitable for
studying their biological activities and for chemical modifications to enhance those activities for health
applications. Although a few relatively simple marine cyanobacterial NPs have been produced in heterologous
hosts such as E. coli, difficulties remain for the expression certain enzymes and of large complex pathways in
phylogenetically distant hosts. We hypothesize that expression of these cyanobacterial genes and gene clusters
in cyanobacterial hosts will overcome this obstacle. The 3 specific aims of this research are as follows. (1)
Establish Leptolyngbya as a broadly applicable genetic platform for identification, expression, and interrogation
of NP pathways. (2) Develop improved genetic tools to enable the transfer, refactoring, and overexpression of
large biosynthetic pathways in platform strains of cyanobacteria. (3) Express two orphan pathways from the
marine cyanobacterial genus Okeania in S. elongatus and Leptolyngbya. New genetic tools and methods will be
created for S. elongatus and Leptolyngbya that will include TAR cloning vectors, shuttle plasmids, chromosomal
integration sites, constitutive and regulated promoters, reporter genes, and antibiotic-resistance markers to
facilitate manipulation of endogenous NP pathways and for the heterologous expression of pathways from other
organisms. This project will combine state-of-the-art approaches in genomics, transcriptomics, bioinformatics of
secondary metabolite pathways, cyanobacterial genetic engineering, and NP chemistry to address knowledge
gaps related to medically important NP biosynthesis in marine cyanobacteria. The project will develop
Leptolyngbya and S. elongatus into broadly useful expression hosts for cyanobacterial secondary-metabolite
enzymes and entire NP biosynthetic pathways, and these hosts and genetic tools will be made available to the
NP research community.

## Key facts

- **NIH application ID:** 9836853
- **Project number:** 5R01GM118815-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** LENA GERWICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $291,678
- **Award type:** 5
- **Project period:** 2017-01-12 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836853

## Citation

> US National Institutes of Health, RePORTER application 9836853, Development of an efficient cyanobacterial platform for heterologous expression and biosynthetic interrogations of natural products. (5R01GM118815-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9836853. Licensed CC0.

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