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

gOnly 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 g/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.T he treatment of life-threatening invasive fungal infections (IFIs) remains a significant challenge to modern medicine (1, 2). Two primary factors contribute to the difficult nature of IFI therapy. First, most IFIs affect people with compromised immune function, and therefore, IFI patients are more reliant on the efficacy of the antifungal drug than immunocompetent patients. Second, the development of effective antifungal drugs is difficult, because many fundamental biological processes are highly conserved between fungi and humans (3). Consequently, identifying molecules that kill the pathogen and spare the host is very challenging. Currently, only three primary classes of antifungal drugs are in clinical use: (i) azole ergosterol biosynthesis inhibitors (e.g., fluconazole [FLU]), (ii) polyene ergosterol binding agents (e.g., amphotericin B), and (iii) echinocandin 1,3-␤-D-glucan synthase inhibitors (e.g., caspofungin). The number of antifungal drugs pales in comparison to the number of distinct classes of antimicrobial agents, and, in fact, there are currently more classes of antiretroviral agents available for the treatment of HIV/AIDS than classes of antifungal drugs (2).The pace of antifungal drug development has been extremely slow. For example, the most recent addition to the antifungal pharmacopeia, the echinocandins, was discovered in the early 1970s and introduced into clinical practice in the early 2000s (3). Furthermore, no new drugs for the treatment of cryptococcal meningitis, one of the most important causes of infectious disease-related deaths in HIV/AIDS patients (4), have been introduced into clinical practice in more than 20 years. In fact, the current gold standard therapy is based on drugs (amphotericin B an...

The antifungal pipeline: a reality check

“…72,73 . In animal models, AR-12 potentiates the activity of fluconazole against C. neoformans infection 72 . The mechanism of action of this compound is not precisely known.…”

Antifungal therapeutics for dimorphic fungal pathogens

“…A more appropriate microdilution method has recently been established for antifungal testing of Histoplasma yeasts, 69 and this methodology produces more accurate data for Histoplasma susceptibility. 73 Despite these caveats, a general profile of the antimicrobial susceptibilities of dimorphic fungi has been developed for amphotericin B and azole-class drugs. Each of the dimorphic fungal pathogens exhibit a similar susceptibility profile for current antifungals with both amphotericin B and azole drugs generally showing potent activity (low minimum inhibitory concentrations; MIC) with some variability in MICs reported for fluconazole (Table 1).…”

“…95 AR-12 has antifungal activity against a broad collection of fungi, including the dimorphic fungal pathogens at concentrations around 4-8 mg/mL. 73 In vitro, AR-12 is fungicidal against Histoplasma yeasts (Rappleye CA, personal communication). These antifungal characteristics combined with AR-12s safety as established in Phase I trials make AR-12 an attractive antifungal candidate for further development.…”

Investigation of aryl isonitrile compounds with potent, broad-spectrum antifungal activity

“…Currently, only three structurally-distinct classes of antifungal drugs are primarily used for treatment of invasive fungal infections – azoles (such as fluconazole), polyenes (such as amphotericin B), and echinocandins (such as caspofungin). 9 All three classes exert their antifungal activity by interfering with synthesis of a key component of the fungal cell membrane (ergosterol synthesis by both azoles and polyenes) or cell wall (β(1,3)-d-glucan synthesis by echinocandins). 9 Azole antifungals, including fluconazole, are considered the drugs of choice given their high oral bioavailability and reduced toxicity to host tissues.…”