# Advancing CRISPR-Cas Technologies for the Discovery and Characterization of Novel Fungal Natural Products

> **NIH NIH R35** · RICE UNIVERSITY · 2022 · $16,814

## Abstract

Abstract
Fungal natural products (NPs) have been a preeminent source of medicine and played pivotal roles as
pharmaceuticals for the treatment of human diseases. The rapid expansion of fungal genome sequences
and the development of bioinformatics tools have enabled the identification of thousands of fungal NP
biosynthetic gene clusters (BGCs), thus providing an unprecedented opportunity to discover new fungal
NPs. However, the discovery of new bioactive fungal NPs remains challenging, due to difficulties in
prioritizing BGCs and genetic manipulations in fungi. In this proposal, we expect to build pipelines to
rapidly discover novel bioactive fungal natural products that can serve as the next generation of drug
candidates for the treatment of human diseases; to do this, we will apply the CRISPR Cas genome editing
technologies and dedicate these tools to the biosynthesis of fungal natural products. To achieve the
research goal, our first direction will focus on identifying and characterizing rarely discovered
ribosomally synthesized and post‐translationally modified peptides (RiPPs) from fungal origins. Due to
RiPPs’ unique biosynthetic machinery, complex chemical characteristics, and important pharmacological
properties, bacterial RiPPs have drawn strong interest from both academia and the pharmaceutical
industry. However, only a handful of RiPPs have been identified from fungi, even though fungi is known
to be a profilic producer of NPs. By characterizing novel biosynthetic enzymes of known RiPPs and new
fungal BGCs identified by bioinformatics analysis, we expect to greatly broaden and deepen our
understanding of the biosynthesis of fungal RiPPs and expand the repertoire of novel fungal RiPP NPs.
Our second direction will focus on expanding and applying CRISPR‐based genome engineering toolkits to
characterize biosynthetic gene clusters from filamentous fungi. CRISPR‐Cas tools have been successfully
demonstrated to be feasible in fungal species but are rarely applied in the investigation of fungal NP
biosynthesis. We will develop complementary sets of CRISPR‐Cas tools for manipulating fungal
biosynthetic gene clusters in both native and heterologous expression hosts. By doing so, we expect to
develop a full set of CRISPR gene‐editing toolkits to rapidly carry out genetic manipulations to study
natural product biosynthesis in filamentous fungi. Together, the two research directions and
collaborative research endeavors through BGC characterization, genetic tool advancement, and new
bioinformatics algorithm development will build a complete pipeline to significantly increase the
repertoire of fungal NPs and analogs, especially fungal RiPPs, making these molecules valuable drug
candidates for human therapeutics.

## Key facts

- **NIH application ID:** 10620458
- **Project number:** 3R35GM138207-03S1
- **Recipient organization:** RICE UNIVERSITY
- **Principal Investigator:** Xue Gao
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $16,814
- **Award type:** 3
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620458

## Citation

> US National Institutes of Health, RePORTER application 10620458, Advancing CRISPR-Cas Technologies for the Discovery and Characterization of Novel Fungal Natural Products (3R35GM138207-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10620458. Licensed CC0.

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