# Gamma Butyrolactones as Biosynthetic Gene Cluster Inducers

> **NIH NIH F32** · PURDUE UNIVERSITY · 2021 · $57,063

## Abstract

Project Summary/Abstract
Historically, natural products (NPs) from Streptomyces have been rich sources for medicines including
antibiotics, antifungals, anticancer agents and many others; however, traditional NP isolation techniques (i.e.
screening culture isolates for antibiotic activity) are no longer effective as evidenced by the high rates of
rediscovery. A significant proportion of the Streptomyces genome (up to 10%) is devoted to genes encoding the
biosynthesis of natural products; however, whole genome sequencing of diverse Streptomyces has revealed the
presence of many transcriptionally inactive (or cryptic) biosynthesis gene clusters (BCGs). These cryptic BCGs
have yet to be characterized which provides strong evidence for the existence of many bioactive NPs that have
not yet been discovered.
A significant gap remains in the strategies available to discover new bioactive NPs from cryptic BGCs. To
maximize the success of NP potential from Streptomyces we propose to study a class of BGC inducers (ɣ-
butyrolactones) to probe the biochemical connection between BGC elicitation and NP production. To this end,
we propose three interrelated aims focusing on (1) the organic synthesis of a library of ɣ-butyrolactones, (2)
development of a novel BGC elicitation assay and (3) isolation and characterization of novel NPs from diverse
Streptomyces. Herein, we have devised synthetic routes for rapid generation of diverse ɣ-butyrolactones. In
parallel, we will develop a green fluorescent protein (GFP) bioassay for both known and novel Ɣ-butyrolactone
receptors predicted via a generated sequence similarity network (SSN). With this in hand, transcription of cryptic
BGCs in diverse Streptomyces cultures will be induced by treatment with synthetic ɣ-butyrolactones. This
proposal will identify novel inducers of BGCs and concurrently result in the identification of novel NPs.
The natural products identified will be tested for antimicrobial and anticancer activity and mechanism of action
studies will be performed in future studies. Overall, this work will result in the identification of bioactive NPs and
will provide a means for the discovery of many more.

## Key facts

- **NIH application ID:** 10141402
- **Project number:** 1F32GM140569-01
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Christina Martinez
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $57,063
- **Award type:** 1
- **Project period:** 2021-01-01 → 2021-11-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141402

## Citation

> US National Institutes of Health, RePORTER application 10141402, Gamma Butyrolactones as Biosynthetic Gene Cluster Inducers (1F32GM140569-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10141402. Licensed CC0.

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