# Mining Actinomycetal Genomes for Natural Product Discovery and Biosynthesis

> **NIH NIH R35** · SCRIPPS FLORIDA · 2020 · $795,502

## Abstract

PROJECT SUMMARY
Natural products (NPs) continue to inspire novel chemistry, biology, and medicine, but the rate of discovery of
novel NPs has slowed dramatically as most gene clusters encoding their biosynthesis are silent when the
microorganisms are cultured under standard laboratory conditions. In this MIRA application, we propose to
discover new NPs by mining actinomycetal genomes, develop enabling technologies to produce the target NPs
in enough quantities for structural elucidation and biological evaluation, and characterize their biosynthetic
machineries to discover new chemistry and enzymology. Our hypotheses have been: (i) genome survey of
the actinomycetale strain collection at The Scripps Research Institute (TSRI) will allow us to identify potential
producers of the targeted NP scaffolds, (ii) genome sequencing of the potential producers for the targeted
biosynthetic gene clusters (BGCs) will allow us to predict the structural novelty of the new NPs, (iii) genetic
manipulation of the most promising BGCs in their native producers or expression of them in heterologous
model hosts will allow us to produce and isolate the new NPs, and (iv) characterization of the biosynthetic
machinery of these new NPs will allow us to discover new chemistry and enzymology. Studies from two past
and two current NIGMS grants have cumulated into (i) the construction of the Natural Products Library at TSRI
that currently consists of ~211,000 microbial strains, ~461,000 crude extracts and partially purified fractions
prepared from selected strains, and ~600 pure NPs, (ii) the establishment of C-1027 and tiancimycin as model
systems for enediyne NP biosynthesis, leinamycin and guangnanmycin as model systems for biosynthesis of
the leinamycin family of NPs (i.e., hybrid peptide-polyketide macrolactams featuring unprecedented sulfur
functionalities), and platensimycin and platencin as model systems for bacterial diterpenoid and thiocarboxylic
acid-containing/derived NP biosynthesis, respectively, and (iii) the identification of 190, 43, 66, and 264 distinct
BGCs, encoding new enediynes, new members of the leinamycin family, new bacterial diterpenoids, and new
thiocarboxylic acid-containing/derived NPs, respectively. These findings set the stage in the current
application to mine the actinomycetal genomes for NP discovery and biosynthesis. The outcomes of this
application include (i) fundamental contributions to genome mining and activation of large BGCs, in native
producers and heterologous model hosts, for NP production and structural diversity by metabolic pathway
engineering, (ii) discovery of new NPs, with privileged scaffolds, to inspire new chemistry, biology, and
medicine, and (iii) new insights into biosynthetic machineries and novel chemistry and enzymology for the
biosynthesis of enediynes, the leinamycin family of NPs, bacterial diterpenoids, and thiocarboxylic acid-
containing/derived NPs. The long-term goal of our research is to understand at a molecu...

## Key facts

- **NIH application ID:** 9851687
- **Project number:** 1R35GM134954-01
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Ben Shen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $795,502
- **Award type:** 1
- **Project period:** 2020-01-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851687

## Citation

> US National Institutes of Health, RePORTER application 9851687, Mining Actinomycetal Genomes for Natural Product Discovery and Biosynthesis (1R35GM134954-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9851687. Licensed CC0.

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