# Overcoming Emerging Aspergillus fumigatus Azole Resistance Via Protease Inhibition

> **NIH NIH R21** · DARTMOUTH COLLEGE · 2020 · $187,459

## Abstract

PROJECT SUMMARY. Infections caused by the filamentous fungus Aspergillus fumigatus and related species
are associated with significant morbidity and mortality despite contemporary antifungal drug therapies. Many
factors contribute to poor treatment outcomes including the physiological state of the fungus at the site of
infection and the global emergence of triazole drug resistant strains. One major regulatory mechanism used by
the fungus to progress disease and resist triazole drug activity is proteolytic activation of the transcriptional
regulator, SrbA. Activation of SrbA in vivo is absolutely required for fungal virulence and intrinsic triazole drug
resistance, as null mutants of SrbA regulatory factors such as the fungal specific activating serine protease
RbdB and E3 ubiquitin ligases (DSCs) are avirulent in animal models of invasive aspergillosis (IA) and have
significant increases in triazole susceptibility. The objective of this proposal in response to RFA-AI-17-036 is to
identify small molecules that inhibit SrbA activation and develop them into advanced therapeutic candidates
with broad-spectrum activity against triazole resistant filamentous fungi. Potent inhibitors of the SrbA-
dependent signaling pathway will be developed for clinical use as an adjunctive therapy in combination with a
triazole antifungal agent that is used to treat IA. The adjunctive therapy is expected to provide several
advantages over triazole monotherapy, including growth inhibition in hypoxic conditions and increased
antifungal activity of the triazole drug in both drug susceptible and drug resistant infections. As the SrbA
pathway is conserved among most human fungal pathogens, some of which are inherently azole resistant, we
anticipate broad spectrum clinical utility beyond infections caused by A. fumigatus. Our approach leverages the
availability of well characterized protease and ligase inhibitor chemical libraries, both known druggable targets
in many disease settings, with the expertise of Microbiotix Inc. and the Cramer Laboratory at Dartmouth. The
R21 phase of this application will utilize high-throughput cell based screens of defined targeted small molecule
libraries to identify and confirm SrbA regulatory protease and/or ligase inhibitors and validate their antifungal
activity, pathway specificity, and mammalian toxicity of early hits and leads. In the R33 phase, validated hits
will be chemically optimized, validated, defined pharmacologically, determine mechanism of action, and finally
proceed to in vivo pharmacologic and toxicology profiling and antifungal efficacy in established murine models
of invasive aspergillosis.

## Key facts

- **NIH application ID:** 9854887
- **Project number:** 5R21AI140878-02
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Robert Andrew Cramer
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $187,459
- **Award type:** 5
- **Project period:** 2019-02-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854887

## Citation

> US National Institutes of Health, RePORTER application 9854887, Overcoming Emerging Aspergillus fumigatus Azole Resistance Via Protease Inhibition (5R21AI140878-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854887. Licensed CC0.

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