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Mass Spectrometry-Guided Genome Mining as a Tool to Uncover Novel Natural Products

Mass Spectrometry-Guided Genome Mining as a Tool to Uncover Novel Natural Products

Published on: March 12, 2020

Comparative transcriptomics as a guide to natural product discovery and biosynthetic gene cluster functionality.

Gregory C A Amos¹, Takayoshi Awakawa^1,2, Robert N Tuttle¹

¹Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA 92093.

Proceedings of the National Academy of Sciences of the United States of America

|December 13, 2017

Summary

Marine bacteria possess many silent gene clusters encoding valuable natural products. Comparative transcriptomics revealed that over half are expressed, identifying regulatory genes linked to silencing and aiding new drug discovery.

Keywords:

Salinispora biosynthetic gene cluster specialized metabolism transcriptomics

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Area of Science:

Microbiology
Genomics
Natural Products Chemistry

Background:

Bacterial natural products are crucial for new medicines.
Most bacterial biosynthetic gene clusters (BGCs) are uncharacterized 'orphan' clusters.
Genome mining aims to link these BGCs to their encoded small molecules, often found to be transcriptionally silent.

Purpose of the Study:

To investigate BGC expression in marine bacteria of the genus *Salinispora* using comparative transcriptomics.
To identify regulatory mechanisms underlying BGC silencing.
To discover novel natural products and their corresponding BGCs.

Main Methods:

Comparative transcriptomics across four *Salinispora* strains.
Analysis of BGC expression levels.
Bioinformatic integration of gene expression and metabolomics data.
Genetic manipulation to confirm gene function.

Main Results:

Over 50% of BGCs showed expression levels suitable for product detection.
Identified regulatory genes associated with BGC silencing by comparing expression profiles.
Confirmed the genetic basis for salinipostins, previously unknown compounds from *Salinispora pacifica*.
Linked salinipostin biosynthesis to its BGC using integrated data.

Conclusions:

Comparative transcriptomics is essential for understanding BGC expression and regulation in bacteria.
BGC silencing is a significant factor in natural product discovery, potentially representing an evolutionary mechanism.
This study successfully linked a BGC to novel compounds, demonstrating the power of integrated genomic and metabolomic approaches.