# Examining the importance of folate biosynthetic enzymes in infectious fungi

> **NIH NIH R21** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $190,000

## Abstract

The folate biosynthetic (FOL) pathway has been targeted with enormous success in the development of
anticancer, antibacterial as well as antiprotozoal drugs. Methotrexate and trimethoprim are potent inhibitors of
mammalian and bacterial dihydrofolate reductase (DHFR) respectively, while a collection of ‘sulfa drugs’ perturb
dihydropteroate synthase function in some bacterial as well as protozoan parasites. Additional antiprotozoal
drugs that target this pathway include the DHFR inhibitors pyrimethamine, proguanil and chlorproguanil, as well
as the DHPS inhibitor dapsone. However, these conventional antifolate drugs have little or no activity upon the
major human fungal pathogens, either because of divergence of the fungal enzymes structure, or permeability
issues that prevent them from entering fungal cells. Furthermore, efforts to adapt conventional antifolate
scaffolds have failed to yield derivatives with the requisite properties of a viable antifungal drug and have focused
almost exclusively upon DHFR, with the remaining enzymes almost completely uncharacterized in any
pathogenic species. We propose that efforts to exploit this pathway for antifungal development should focus
upon the FOL biosynthetic enzymes that have not yet been the subject of significant investigation and that are
completely absent from mammals. In addition, they should seek novel antifolate scaffolds that are active upon
whole fungal cells. The objective of this proposal is to substantiate the validity and feasibility of targeting fungal
Fol1p and Fol3p, which together possess four FOL enzyme activities that are entirely absent from mammals. In
aim 1 we will confirm the essentiality of the Fol1p and Fol3p proteins in two of the most prevalent human fungal
pathogens, the yeast Candida albicans and the infectious mold Aspergillus fumigatus, and establish the potential
antifungal efficacy that can be achieved in targeting these enzymes using mouse models of invasive fungal
infection. In aim 2 we will establish and validate high-throughput compatible cell-based and biochemical assays
that can be applied to identify small molecules inhibitors of these enzymes activity. Collectively, these studies
will determine if FOL enzymes that are absent from mammals can provide chemically tractable and efficacious
targets to devise new antifungal therapies and potentially yield lead compounds that can form the basis of such
medications.

## Key facts

- **NIH application ID:** 10308098
- **Project number:** 5R21AI156611-02
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Glen Palmer
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $190,000
- **Award type:** 5
- **Project period:** 2020-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308098

## Citation

> US National Institutes of Health, RePORTER application 10308098, Examining the importance of folate biosynthetic enzymes in infectious fungi (5R21AI156611-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10308098. Licensed CC0.

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