# Development of non-toxic amphotericin B derivatives targeting invasive fungal infections

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $714,404

## Abstract

1. Project Summary / Abstract
 Invasive fungal infections (IFI) are a leading cause of death in the growing number of
immunocompromised patients, and successful therapy is notoriously difficult. Leading FDA-approved
antifungal classes are limited by inadequate clinical efficacy, which is often due to dose-limiting toxicities,
emerging resistance, drug-drug interactions, and the need for therapeutic monitoring. New antifungals with
robust activity against a broad spectrum of pathogens, minimal susceptibility to resistance, and limited side
effects are needed. Amphotericin B (AmB) demonstrates dose-dependent killing, is fungicidal, has
exceptionally broad spectrum, and has no reported development of resistance. However, the commercially
available forms of AmB, including AmBisome®, have both acute and chronic toxicities that preclude safe use at
high doses. This toxicity hinders realization of the full clinical potential of AmB. Our goal is to develop a
chemically modified AmB derivative with a broad spectrum of robust fungicidal activity, lack of resistance, and,
most importantly, limited toxicity. This will enable clinicians to safely employ high-dose treatment protocols to
more effectively treat IFI. Overturning half a century of prior thinking, we found that AmB primarily kills both
fungal and human cells by simply binding ergosterol and cholesterol, respectively. Guided by this insight, we
recently designed a new AmB derivative, C2’epiAmB, which selectively binds ergosterol over cholesterol.
Accordingly, C2’epiAmB retains good fungicidal activity against many pathogens, and is non-toxic to human
primary renal epithelial cells (hRECs), mice, and rats at the highest doses tested. However, C2’epiAmB also
has important limitations with respect to potency and pathogen scope. Earlier studies from our labs identified
AmB derivatives bearing urea motifs at C16 which show increased antifungal potency but retain unacceptable
toxicities. In this research program, we will combine the toxicity-eliminating C2’ modification in C2’epiAmB with
efficacy-promoting urea modifications at C16 to develop a new class of hybrid polyene fungicidal agents that
are both non-toxic and highly effective in eradicating IFI. A representative hybrid derivative that we recently
synthesized, C2'epiAmBAU, has excellent potency against a series of important pathogens and minimal
toxicity in hRECs. Building on these and many other encouraging preliminary results, we now plan to
synthesize a family of C2’epiAmBUreas and extensively characterize them in state-of-the-art biophysical,
mechanistic, resistance, efficacy, and toxicity studies, to identify the most promising candidates for enabling a
new ‘high-dose’ clinical paradigm for better treating IFI. To accomplish all these goals, we have assembled a
world-class multidisciplinary team of experts in chemical synthesis, antifungal development, pharmacokinetics,
molecular mycology, and the clinical management of IFI. At the end of this...

## Key facts

- **NIH application ID:** 10183149
- **Project number:** 5R01AI135812-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** David R Andes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $714,404
- **Award type:** 5
- **Project period:** 2018-06-08 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183149

## Citation

> US National Institutes of Health, RePORTER application 10183149, Development of non-toxic amphotericin B derivatives targeting invasive fungal infections (5R01AI135812-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10183149. Licensed CC0.

---

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