# Rapid dissection of the biosynthesis of antiMRSA antibiotics produced in co-culture by extremophilic fungi through the development of Fungal Artificial Chromosomes

> **NIH NIH R44** · INTACT GENOMICS, INC. · 2024 · $960,097

## Abstract

PROJECT SUMMARY. The economic and social burden of the treatment of infectious and
chronic diseases is enormous, >$300B annually. The ongoing COVID-19 pandemic alone will
cost the U.S. economy roughly $8 trillion over the next decade without an effective drug to date.
The emergence of drug resistant microbes, the diminishing supply of novel classes of antibiotics,
and the dramatic reduction in R&D of anti-infective, anti-proliferation and anti-inflammatory
agents have further amplified public health concerns. Fungi are prolific producers of anti-
microbial secondary metabolites (SM) and since the turn of the century have provided 45% of
bioactive molecules from all microbial sources. However, environmental filamentous fungi and
fungal SM biosynthetic gene clusters (BGCs) remain largely untapped due to difficulties in
efficiently handling and expressing these SM BGCs. This research proposal will advance the
science of functional SM metagenomics, and will further advance our newly-developed fungal
artificial chromosome (FAC) technology by integrating Next-Gen Sequencing (NGS), artificial
intelligence (AI), FAC heterologous expression, and direct Nuclear Magnetic Resonance (NMR)
analysis. Our methodologies enable precise capture of full-length SM BGCs from any fungus,
and heterologous expression of large intact silent SM BGCs-containing FAC clones for high
yields of natural products (NPs). Our goals are to improve the prediction of novel BGCs and
their compound production, and to discover novel NPs for clinical development of novel
antibiotics and other drug leads. In proof-concept research, we successfully predicted and
captured the FAC-BGC of novel antibiotic berkeleylactone A and 136 BGCs from two different
fungi by FAC-NGS. Phenomenally, we achieved at least 60% yields of discreet NP compounds
as FAC crude extracts by heterologous expression of 5 of 17 BGC-FACs. We also elucidate the
structures of 15 NP molecules with diverse activities, including TWO novel compounds by direct
NMR analysis of FAC crude extracts, due to the high yield of some compounds. In this Phase II
study, we will further improve our in-house FAC-NGS-AI pipeline to better predict novel fungal
BGCs and their NPs, increasing the compound hit rate to 50~70% with high yield. We will
completely dissect the berkeleylactone BGC and discover novel derivatives of this new antibiotic
of homologous BGCs of other fungi. We will also study twelve fungi (ten fungi with no reference
genomic sequences available) with an estimated 800 BGCs. This technology should improve
fungal SM discovery 100~1000 fold and result in the discovery of at least five novel antibiotics,
and other drug leads from un-studied/un-sequenced fungi of the toxic Berkeley Pit.

## Key facts

- **NIH application ID:** 10879091
- **Project number:** 5R44AI170419-03
- **Recipient organization:** INTACT GENOMICS, INC.
- **Principal Investigator:** Chengcang Charles Wu
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $960,097
- **Award type:** 5
- **Project period:** 2022-07-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879091

## Citation

> US National Institutes of Health, RePORTER application 10879091, Rapid dissection of the biosynthesis of antiMRSA antibiotics produced in co-culture by extremophilic fungi through the development of Fungal Artificial Chromosomes (5R44AI170419-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10879091. Licensed CC0.

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