Journal article
The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis
Antimicrobial agents and chemotherapy, Vol.60(12), pp.7115-7127
12/2016
DOI: 10.1128/AAC.01061-16
PMCID: PMC5118990
PMID: 27645246
Abstract
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.
Details
- Title: Subtitle
- The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis
- Creators
- Kristy Koselny - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USAJulianne Green - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USALouis DiDone - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USAJustin P Halterman - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USAAnnette W Fothergill - Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USANathan P Wiederhold - Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USAThomas F Patterson - South Texas Veterans Health Care System, San Antonio, Texas, USAMelanie T Cushion - Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USAChad Rappelye - Department of Microbiology, The Ohio State University, Columbus, Ohio, USAMelanie Wellington - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USADamian J Krysan - Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.60(12), pp.7115-7127
- DOI
- 10.1128/AAC.01061-16
- PMID
- 27645246
- PMCID
- PMC5118990
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Grant note
- N01AI60011 / NIAID NIH HHS K12 HD068373 / NICHD NIH HHS R01 AI097142 / NIAID NIH HHS
- Language
- English
- Date published
- 12/2016
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984093369202771
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