# Broad spectrum antifungals targeting fatty acid biosynthesis

> **NIH NIH R33** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2021 · $1

## Abstract

An estimated 1.5 million people die each year from invasive fungal infections, and many millions more are
afflicted by debilitating mucosal and subcutaneous mycoses. Current antifungal therapies have serious
deficiencies including poor efficacy, limited spectrum of activity, patient toxicity and the emergence of resistant
fungi. Consequently, mortality rates have remained disturbingly high. New and improved therapeutic options
are desperately needed to improve patient outcomes and redress the rise of resistance. Yet the discovery and
development of new pharmocotherapies remains a frustratingly inefficient process. The objective of phase 1
(R21) of this proposal is to apply an unconventional chemical screening strategy to identify physiologically
active, and fungal selective inhibitors of fatty acid (FA) biosynthesis. Our approach will focus upon fatty acid
synthase (FAS) and the Ole1p FA desaturase, both of which have a fundamentally different structural
organization and functional constitution compared to their mammalian counterparts. FAS and Ole1p are both
essential for the viability of infectious fungi in vivo, including the prevalent human pathogens Candida albicans
and Cryptococcus neoformans. We propose to exploit these targets to develop a new class of efficacious and
broad spectrum antifungal therapy. A new whole-cell based approach developed within our lab termed Target
Abundance based Fitness Screening (TAFiS), will be applied to identify specific inhibitors of C. albicans FAS
and Ole1p. This method facilitates the selection of chemical probes that interact with a specific target protein
within intact cells, thereby combining the advantages of traditional target- and cell- based screens into a single
high-throughput assay. Inhibition of FA synthesis will be confirmed through biochemical analysis of treated
fungal and mammalian cells, and those with fungal selective activity identified. In phase 2 (R33), the antifungal
potency, selectivity and ADME properties of lead compounds will be optimized, and structure-activity
relationships established. The spectrum of activity of selected leads will also be tested against important
human fungal pathogens, and to isolates resistant to current antifungal drugs. Finally, the biopharmaceutic,
pharmacokinetic and toxicologic properties of selected leads will be assessed before antifungal efficacy is
tested in a mouse model of disseminated fungal infection. Completion of this study will facilitate the
development of a new generation of antifungal drugs that can cure invasive fungal infections that are refractory
to current treatment options.

## Key facts

- **NIH application ID:** 10061536
- **Project number:** 5R33AI127607-05
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Glen Palmer
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2016-12-08 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10061536

## Citation

> US National Institutes of Health, RePORTER application 10061536, Broad spectrum antifungals targeting fatty acid biosynthesis (5R33AI127607-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10061536. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*