# Novel Broad Spectrum Inhibitors of Dihydrofolate Reductase (DHFR) for Treatment of Infections from High Threat Fungal Pathogens

> **NIH NIH R44** · KATHERA BIOSCIENCE INC. · 2024 · $298,530

## Abstract

Project Summary
There is a worldwide need for improved treatment of systemic, life-threatening fungal infections.
Current therapies are limited by the small number of approved drugs, toxicities, drug-drug
interactions, mode of administration, and growing problems of drug resistance and emerging
pathogens. Treatment also suffers from a lack of rapid clinical diagnoses, leading to dependence
on broad-spectrum antifungal drugs. Moreover, existing antifungal drug classes target membrane
and cell wall integrity, and there is a need to develop drugs against targets with new modes of
action to minimize cross resistance. Available evidence suggests dihydrofolate reductase (DHFR)
might be one such target. Commercial DHFR inhibitors are available for other therapeutic
indications (immunology, oncology, antibacterial, antiparasitic). Bactrim® is the only available
DHFR inhibitor for fungal infections but has a very narrow spectrum of activity (Pneumocystis
jirovecii and Paracoccidioides spp.), despite DHFR being an essential enzyme that is highly
conserved in fungal pathogens. As demonstrated in the current work, Candida spp., Aspergillus
spp., Cryptococcus spp., rare molds, Mucorales and dermatophytes are susceptible to DHFR
inhibition, and the DHFR mechanism of action is complementary to the targets of existing
antifungals. Fungal DHFR inhibitors have been identified that inhibit the enzyme selectively and
fungal cell growth in vitro, and fungal DHFRs differ in structure sufficiently from human DHFR
indicating that development of selective DHFR drugs is feasible. The specific aims of this Fast
Track proposal are to (1) reduce serum antagonism of our initial fungal DHFR inhibitors and
demonstrate in vivo efficacy, (2) optimize a lead fungal DHFR compound or series to select a
potential development candidate and (3) validate a fungal DHFR lead (or leads) and select a
single candidate for IND-enabling studies. The approach will enable a robust lead optimization
program to accomplish the aims and will include analog synthesis and computational chemistry,
biochemical, structural, and modeling studies, whole-cell assays, in vivo models (i.e., efficacy,
pharmacokinetic and pharmacodynamic) and in vitro ADME/Safety profiling to synthesize and test
inhibitors against fungal and human DHFR enzymes, fungal pathogens, and mammalian cells.
The outcomes will advance this program into IND-enabling studies (Phase IIB). The long-term
objective is to develop fungal-selective DHFR inhibitors into a new class of broad-spectrum
antifungal drugs.

## Key facts

- **NIH application ID:** 10820639
- **Project number:** 1R44AI181163-01
- **Recipient organization:** KATHERA BIOSCIENCE INC.
- **Principal Investigator:** Stephen Parent
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $298,530
- **Award type:** 1
- **Project period:** 2024-01-02 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820639

## Citation

> US National Institutes of Health, RePORTER application 10820639, Novel Broad Spectrum Inhibitors of Dihydrofolate Reductase (DHFR) for Treatment of Infections from High Threat Fungal Pathogens (1R44AI181163-01). Retrieved via AI Analytics 2026-07-31 from https://api.ai-analytics.org/grant/nih/10820639. Licensed CC0.

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