# Development of a Bacterial Host for Natural Product Discovery and Production

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $423,828

## Abstract

Project Summary
Molecules isolated from living systems have consistently served as leads in drug discovery. However, two of the
main challenges of drug discovery from natural products are the high rate of rediscovery of known compounds
using traditional technologies and low yields. Recent advances in genome sequencing and synthetic biology
have spurred a renewed interest in natural product discovery in the private and academic sectors. For instance,
genome mining of underexplored taxa increases the chances of novel compound discovery. Moreover, robust
host organisms can facilitate discovery efforts by overcoming the common low-yield hurdle. Bacteria belonging
to the Burkholderiales order of -Proteobacteria are an emerging source of natural products. We have previously
achieved high yield production of autologous polyketide-nonribosomal peptide spliceostatins in a Burkholderia
species. We propose to understand, develop, and apply this strain as a host to discover and produce natural
products from Burkholderiales and potentially other -Proteobacteria. Although Escherichia coli has long been
used as a model bacterial host, the synthetic biology community is moving away from the idea that “one host fits
all” to instead have hosts tailored to the source of biosynthetic gene clusters. We hypothesize that the
Burkholderia sp. in question can be used as a host to streamline the discovery process by producing
heterologous natural products in high yields. Our preliminary data supports this hypothesis as heterologous
expression of a model gene cluster encoding the lasso peptide capistruin in this strain led to capistruin production
in yields that are at least 65-fold, and up to 580-fold higher than with E. coli. In Aim 1 we propose to
test/understand the host by a) testing the breath of the host in terms of source genera within the Burkholderiales
and other -Proteobacteria while discovering lasso peptides; and b) investigating the regulation of autologous
spliceostatin biosynthesis with the ultimate goal of deriving regulatory parts for heterologous pathway
construction. In Aim 2, we will develop the host as a tool for natural product discovery by discovering and
characterizing a promoter library and by generating a minimized genome. In Aim 3 we will apply the host by
discovering natural products from a newly built Burkholderiales environmental collection. This project is expected
to provide tools that will streamline and accelerate natural product discovery from a promising yet underexplored
source. The tools and knowledge obtained will be applied to discover novel, bioactive natural products via
genome mining of a Burkholderiales strain collection.

## Key facts

- **NIH application ID:** 10051448
- **Project number:** 1R01GM129344-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Alessandra S Eustaquio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,828
- **Award type:** 1
- **Project period:** 2020-09-20 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051448

## Citation

> US National Institutes of Health, RePORTER application 10051448, Development of a Bacterial Host for Natural Product Discovery and Production (1R01GM129344-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10051448. Licensed CC0.

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