# Exploring a New Dimension of Microbial Secondary Metabolism

> **NIH NIH R01** · PRINCETON UNIVERSITY · 2021 · $309,483

## Abstract

ABSTRACT
 Bacterial natural products have provided an immense source of therapeutic agents and driven innovation
in chemistry, biology, and pharmacology. In the past decade, it has become evident that the capacity of
bacteria to synthesize natural products was vastly underestimated. Advances in genome and transcriptome
sequencing combined with bioinformatic methods have shown that most biosynthetic genes are not
expressed or, at best, sparingly expressed during standard laboratory growth; their products are therefore not
synthesized at sufficient titers for detection and structural/functional characterization. These so-called ‘silent’
or ‘cryptic’ biosynthetic gene clusters outnumber constitutively active ones by a factor of 5-10. As such, they
represent a new dimension of bacterial metabolism, and unlocking it will allow access to a wealth of new
natural products and to deeper insights into microbial physiology and biochemistry.
 We recently contributed the High-Throughput Elicitor Screening (HiTES) methodology toward the
discovery of cryptic metabolites. In this approach, small molecule libraries are screened to identify inducers
of selected silent gene clusters. With elicitors identified, the cryptic metabolite and the regulation of the silent
cluster can be investigated. Several aspects of HiTES remain unexplored and they form the basis for the
current application: HiTES has only been applied to Burkholderia spp. and a few actinomycetes. Other prolific
genera have not yet been targeted. Moreover, the mechanism underlying HiTES remains to be determined.
Low-dose antibiotics have repeatedly been identified as the most effective elicitors, but the regulatory
pathways that underpin this response remain to be elucidated. In the current application, we seek address
these topics by expanding HiTES to prolific and understudied bacterial genera for the discovery of new, cryptic
natural products with desired biological activities, and by elucidating the mechanisms with which low-dose
antibiotics elicit cryptic metabolite biosynthesis, focusing on the β-lactam antibiotics and their stimulatory
effect on the model organism Burkholderia thailandensis. Collectively, these studies will shed light on an
emerging dimension of bacterial secondary metabolism, unearth new regulatory circuits that drive expression
of silent gene clusters, and provide novel natural products as possible therapeutic leads and sources of
biosynthetic and pharmacological investigations.

## Key facts

- **NIH application ID:** 10298182
- **Project number:** 1R01GM140034-01A1
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Mohammad R Seyedsayamdost
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $309,483
- **Award type:** 1
- **Project period:** 2021-07-05 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298182

## Citation

> US National Institutes of Health, RePORTER application 10298182, Exploring a New Dimension of Microbial Secondary Metabolism (1R01GM140034-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10298182. Licensed CC0.

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