The celecoxib derivative AR-12 has broad-spectrum antifungal activity in vitro and improves the activity of fluconazole in a murine model of cryptococcosis

Kristy Koselny, Julianne Green, Louis DiDone, Justin P. Halterman, Annette W. Fothergill, Nathan P. Wiederhold, Thomas F. Patterson, Melanie T. Cushion, Chad Rappelye, Melanie Wellington, Damian J. Krysan

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7115-7127
Number of pages13
JournalAntimicrobial agents and chemotherapy
Volume60
Issue number12
DOIs
StatePublished - Dec 2016

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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