# Natural Product Genome Mining

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $74,114

## Abstract

Project Summary / Abstract
Natural products continue to provide important drug leads in medicine. While the majority of clinical
antibiotics are derived from bacterial natural products, the emergence of antibiotic resistance emphasizes
the need to discover new antimicrobial leads. This renewal application builds upon a productive
collaboration between the Jensen (microbiology/bioinformatics) and Moore (biosynthesis/natural
products chemistry) laboratories to address this need through the mining of microbial genomes and
metagenomes for new bioactive compounds. We have prioritized two diverse groups of chemically gifted
marine bacteria for study from a collection of >10,000 strains collected across the world’s oceans. We
continue our efforts with the obligate marine actinomycete Salinispora, which produces the potent
proteasome inhibitor salinosporamide A (Marizomib) that is presently in phase III trials to treat brain
cancer. Here we capitalize on the recent identification of six new Salinispora species and 99 new
genomes to expand our efforts in this unique taxon. We further expand our genome mining efforts to
include the MAR4 lineage, a second chemically gifted group of marine bacteria for which we are uniquely
situated to explore with 42 new genomes. This lineage shows the first evidence that marine adaptations
are linked to natural product biosynthesis and includes at least six new species. We have identified
hundreds of orphan biosynthetic gene clusters (BGCs) in these two groups and prioritized them as lead
discovery targets. We have further taken this program into new directions by mining BGCs directly from
environmental DNA (eDNA) using a nontargeted metagenomic approach that provides unbiased access
to the biosynthetic potential of microbial diversity. These samples originate from both shallow tropical
ocean sediments (1515 natural product BGCs already assembled) as well as deep sea sediments (down
to 2000 meters) that are being collected for this program and have yet to be explored for natural products
research. We will maximize access to these unique resources and employ innovative techniques in
genome mining and synthetic biology to prioritize the targeted discovery of new antibiotic leads such as
beta-lactone-containing products from eDNA that are predicted to inhibit protease virulence factors in
Gram(-) bacteria. These genome mining efforts are governed by a logical workflow that prioritizes novel
antibiotic discovery from poorly explored microbial resources.

## Key facts

- **NIH application ID:** 10616171
- **Project number:** 3R01GM085770-14S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** PAUL R JENSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $74,114
- **Award type:** 3
- **Project period:** 2009-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10616171

## Citation

> US National Institutes of Health, RePORTER application 10616171, Natural Product Genome Mining (3R01GM085770-14S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10616171. Licensed CC0.

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