The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis
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Only one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity, including activity against yeasts (e.g., Candida albicans , non- albicans Candida spp., Cryptococcus neoformans ), molds (e.g., Fusarium , Mucor ), and dimorphic fungi ( Blastomyces , Histoplasma , and Coccidioides ) with MICs of 2 to 4 μg/ml. AR-12 is also active against azole- and echinocandin-resistant Candida isolates, and subinhibitory AR-12 concentrations increase the susceptibility of fluconazole- and echinocandin-resistant Candida isolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad-spectrum antifungal activity.
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Pitavastatin interacted synergistically with fluconazole against C. albicans SC-TAC1G980E, which has a gain-of-function mutation in TAC1.
“Similarly, pitavastatin interacted synergistically with fluconazole against C. albicans SC-TAC1G980E strain, which has a gain of function mutation in TAC1, a positive transcription regulator for the ABC (ATP Binding Cassette) membrane transporters29–31.”
From Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species (2020) · cites this paper as [31]
The pitavastatin-fluconazole combination failed to display synergistic interactions against C. albicans TWO7241 (increased ERG11 and MDR1) and SC-MRR1P683S (MRR1 gain-of-function).
“However, the pitavastatin-fluconazole combination failed to display similar interactions against strain TWO7241, which exhibits increased mRNA levels of both ERG11 and MDR1, and strain SC-MRR1P683S which has a gain of function mutation in MRR1, a positive transcription regulator for the MFS (Major Facilitator Superfamily) membrane transporters29–31.”
From Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species (2020) · cites this paper as [31]
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References 56 · Cited by 83
- Authors
- Koselny, K., Green, J., DiDone, L., Halterman, J. P., Fothergill, A. W., Wiederhold, N. P., Patterson, T. F., Cushion, M. T., Rappelye, C., Wellington, M., & Krysan, D. J.
- Affiliations
- University of Rochester Medicine (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Cincinnati (US)
- The Ohio State University (US)
- ORCID
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2016-12
- Volume
- 60
- Issue
- 12
- Pages
- 7115-7127
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC5118990
- OpenAlex
- W2522400009
- Cited by
- 83
- References
- 56
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 9 · 2023: 11 · 2022: 6 · 2021: 7 · 2020: 16 · 2019: 6 · 2018: 8 · 2017: 10 · 2016: 1
- FWCI
- 7.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (1R01AI097142, 5K12HD068373, HHS272201000018I)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- celecoxib derivative, antifungal activity, Cryptococcus neoformans, cryptococcosis, fluconazole synergy, Candida albicans, non-albicans Candida, azole resistance, echinocandin resistance, dimorphic fungi, molds, fungicidal activity, novel antifungal agents
- MeSH terms
- Celecoxib, Caspofungin, Animals, Antifungal Agents, Candida, Cryptococcosis, Cryptococcus neoformans, Disease Models, Animal, Drug Evaluation, Preclinical, Drug Synergism, Male, Mice, Inbred Strains, Microbial Sensitivity Tests, Pneumocystis, Pyrazoles, Saccharomyces cerevisiae, Sulfonamides, Fluconazole, Gene Expression Regulation, Fungal, Drug Resistance, Fungal, Echinocandins, Lipopeptides
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