Antifungal Efficacy of GM237354, a Sordarin Derivative, in Experimental Oral Candidiasis in Immunosuppressed Rats

Abstract

GM237354 is a novel sordarin derivative with a broad spectrum of potent activity against a wide range of fungi. The members of this new class of antifungal agents act as potent inhibitors of fungal protein synthesis. In this study, the therapeutic effects of GM237354 were investigated in a novel experimental oral Candida albicans infection model in immunosuppressed rats. The animals were immunosuppressed with dexamethasone in their drinking water and infected on three alternate days. GM237354 was given three times per day for seven consecutive days at 1.25, 2.5, 5, or 10 mg/kg of body weight per dose. In addition, to provide a preliminary idea of the correlation between regimen administration and therapeutic efficacy, GM237354 was administered to two additional groups of rats at 5 mg/kg once or twice a day for 7 days. The drug efficacy was assessed microbiologically, histologically, and by a morphometric study of lesions. Evident agreement was observed among results obtained by the different methods in all of the animals studied. Microbiologically, the efficacy of GM237354 was determined by measuring the number of C. albicans organisms in the oral cavities of rats in the middle (day 4) and at the end (day 7) of the treatment. GM237354 administered at 5, 7.5, 10, 15, or 30 mg/kg/day for 7 days significantly reduced the number of CFU in the oral cavities of treated rats compared with the number of CFU in the oral cavities of the untreated controls. A significant reduction was also observed when GM237354 was administered at 7.5, 10, 15, or 30 mg/kg/day for 4 days. Furthermore, C. albicans was not detected in oral swabs from any infected rats after 1 week of treatment when GM237354 was administered at 15 or 30 mg/kg/day or after 4 days of treatment at 30 mg/kg/day. Histologically, untreated control animals showed extensive colonization of the epithelium of the dorsal tongue by numerous hyphae. Animals treated with GM237354 at 7.5 mg/kg/day showed small areas with superficial hyphal penetration into the epithelium that produced intraepithelial microabscesses. However, animals treated with GM237354 at 15 mg/kg/day showed multiple regenerative areas of the covering epithelium, and only focalized zones of the tongue surface were occupied by hyphae. No hyphal colonization of the epithelium was seen in rats treated with GM237354 at 30 mg/kg/day and which showed extensive areas of epithelial regeneration of the tongue. The histopathology findings were confirmed by morphometry studies, and the percentage of epithelium occupied by C. albicans hyphae decreased from 17.5% in the control group to 4.8 and 0.1% in animals treated with GM237354 at 7.5 and 15 mg/kg/day, respectively. These results demonstrated that the sordarin derivative GM237354 was effective against experimental oral candidiasis in immunosuppressed rats, and further studies are needed to determine the potential of GM237354 for use in the treatment of this infection in humans.

A Novel Murine Model of Oral Candidiasis with Local Symptoms Characteristic of Oral Thrush

“…Recently, Martinez et al (15) showed an oral candidiasis model in rats which mimics tongue lesions found in patients. Our model is easier to make and handle than their model.…”

Antifungal Activities of Two New Azasordarins, GW471552 and GW471558, in Experimental Models of Oral and Vulvovaginal Candidiasis in Immunosuppressed Rats

“…Furthermore, oral and vaginal candidiasis models have been shown to afford a simple, reliable, and highly reproducible method for studying the efficacies of new antifungal agents (17,20). On the other hand, strain-related differences in C. albicans pathogenicity in the rat mucosa have been described; consequently, we have used a well-characterized C. albicans strain that has been widely used in previous therapeutic and pharmacodynamic studies in rodents, where its pathogenic properties have been well demonstrated (1,13,14). In the present study, immunosuppression in the VVC model ensured homogeneous and chronic infection in the rats.…”

“…Oral infection in rats was induced basically as reported by Jones and Adams (11) with some modifications (14). Rats were immunosuppressed, starting 1 week before initiation of experimental infection and continued throughout the experiment, by administering dexamethasone (Fortecortin; Merck Laboratories, Madrid, Spain) in drinking water at a dose of 0.5 mg per liter.…”

“…Therapeutic efficacy studies were performed against C. albicans 4711E, a clinical isolate used in previous in vivo studies (1,13,14). C. albicans 4711E was stored at Ϫ80°C in Sabouraud dextrose broth containing 15% glycerol in our laboratory until used.…”

“…Sordarin derivatives have demonstrated potent and relatively broadspectrum antifungal activity in several in vitro (10) and in vivo (1,13,14) studies. A further evolution of this class of compounds has led to a new family of substances called azasordarins.…”