title: The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis.
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.
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Koselny
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Julianne
authors.initials: J
authors.lastname: Green
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: DiDone
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Halterman
authors.affiliation: Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Annette W
authors.initials: AW
authors.lastname: Fothergill
authors.affiliation: Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Wiederhold
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Patterson
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Melanie T
authors.initials: MT
authors.lastname: Cushion
authors.affiliation: Department of Microbiology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Rappelye
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wellington
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA damian_krysan@urmc.rochester.edu.|Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Krysan
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects / Q000235:genetics; D000077336:Caspofungin; D000068579:Celecoxib / Q000737:chemistry; D003453:Cryptococcosis / Q000188:drug therapy*; D003455:Cryptococcus neoformans / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D025141:Drug Resistance, Fungal / Q000187:drug effects; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology; D015725:Fluconazole / Q000494:pharmacology*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D055666:Lipopeptides / Q000494:pharmacology; D008297:Male; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D011010:Pneumocystis / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; C500894:OSU 03012; D011720:Pyrazoles; D013449:Sulfonamides; D015725:Fluconazole; D000077336:Caspofungin; D000068579:Celecoxib