# Rapid discovery of thousands of intact biosynthetic gene pathways for bioactive natural product compounds from un-sequenced filamentous fungi using a novel FAC-NGS tool

> **NIH NIH R44** · INTACT GENOMICS, INC. · 2022 · $1,000,000

## Abstract

Project Summary/Abstract
The goal of this project is to develop a highly rigorous technology platform utilizing lichen and un-
sequenced fungi to revive the discovery pipeline for fungal-derived therapeutics capable of
treating chronic infections and health conditions. The emergence of drug resistant microbes, the
diminishing supply of novel classes of antibiotics, and the dramatic reduction in discovery and
development of natural products (NPs, also termed secondary metabolites, SMs) and other small
molecule compounds from bacteria and fungi for anti-infective, anti-proliferation and anti-
inflammation agents since 1960s have amplified a serious public health concern championed by
the CDC and WHO. We posit that the revival of large-scale drug discovery pipelines using under-
exploited microbes including lichen fungal symbionts and un-sequenced fungi will provide a new
cadre of novel drug leads and solutions towards the antibiotic-resistance crisis. Fungal SMs are
also important sources of anticancer compounds among other widespread clinical uses. However,
only 1% or less of filamentous fungi have been sequenced and high throughput sequencing has
shown that only about 10% of fungal SM-biosynthetic gene clusters (BGCs) are expressed under
laboratory conditions. Therefore, revolutionary technologies and tools are urgently needed to
discover and more effectively dissect the biosynthesis of fungal SMs in order to more efficiently
access novel fungal metabolites as potential pharmaceutical agents. Recently, we developed a
novel fungal artificial chromosome/mass spectrometry (FAC-MS) method that allows the direct
capture, heterologous expression and chemical analysis of an entire set of large intact SM-BGCs
from sequenced fungi as shown in Clevenger et al., Nat. Chem. Biol, 2017. We have also shown
that shuttle bacterial artificial chromosome (BAC) technology combined with BAC pooling,
indexing, and next-gen sequencing (NGS) can achieve 100kb-linked sequencing and assembly.
Therefore, in this project, we will develop an innovative fungal technology platform by
integrating FAC-MS with BAC/NGS sequencing and bioactivity profiling to prove the concept that
novel bioactive SMs can be captured from hard to grow (e.g. lichen fungal symbionts, Phase I)
and un-sequenced fungi (Phase II). This technology should improve fungal SM discovery
100~1000 fold and result in the discovery of at least 5 novel antimicrobial drug leads from lichen
and un-sequenced fungi.

## Key facts

- **NIH application ID:** 10348139
- **Project number:** 5R44AI140943-04
- **Recipient organization:** INTACT GENOMICS, INC.
- **Principal Investigator:** Jin Woo Bok
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,000,000
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348139

## Citation

> US National Institutes of Health, RePORTER application 10348139, Rapid discovery of thousands of intact biosynthetic gene pathways for bioactive natural product compounds from un-sequenced filamentous fungi using a novel FAC-NGS tool (5R44AI140943-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10348139. Licensed CC0.

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