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

Abstract

Sordarins constitute a new class of antifungal agents with a novel mechanism of action involving the selective inhibition of fungal protein synthesis. A further evolution of this class of antifungals has led to a new family of sordarin derivatives called azasordarins. The therapeutic efficacies of two new azasordarins, GW471552 and GW471558, were studied in experimental models of oral and vulvovaginal candidiasis in immunosuppressed rats. In all cases rats were immunosuppressed with dexamethasone in the drinking water. Oral candidiasis was established by inoculating 0.1 ml of a yeast suspension containing 5 ؋ 10 8 cells of Candida albicans 4711E with a cotton swab on three alternate days. Vulvovaginal candidiasis was established in ovariectomized and estrus-induced rats by intravaginal inoculation of 10 7 CFU of C. albicans 4711E in 0.1 ml of saline. GW471552 and GW471558 were administered at 1, 5, and 10 mg/kg of body weight via the subcutaneous route. In oral candidiasis, azasordarins were administered each 8 h for 7 consecutive days, while in vaginal candidiasis the compounds were given each 4 h for 3 consecutive days. Antifungal activity of azasordarins was assessed by colony counts and by histological examination 1 day after treatment. In the oral infection model, GW471552 and GW471558 administered at 5 mg/kg significantly reduced (P < 0.05) the number of CFU of C. albicans compared with untreated controls. In addition, GW471552 and GW471558 given at 10 mg/kg eradicated C. albicans from the oral cavities of 100% of infected animals. Against vulvovaginal infection, both compounds showed significant therapeutic efficacy. GW471552 was able to eradicate the vaginal fungal burden at a dose of 10 mg/kg, and it significantly reduced the number of CFU of C. albicans in vaginas of rats treated with a dose of 5 mg/kg (P < 0.05). GW471558 showed greater efficacy, eradicating the fungal burden of 100% of infected rats at a dose of 5 mg/kg and significantly reducing (P < 0.05) the C. albicans vaginal counts even at a dose of 1 mg/kg. In both therapeutic efficacy studies, the histological findings confirmed the microbiological results. The experimental results presented show that the tested azasordarins are effective against oral and vulvovaginal candidiasis in immunosuppressed rats and could be promising antifungal agents for use in humans.

Antifungal activity of silver nanoparticles in a murine model of oral candidiasis

“…The procedure adopted in the present study was successful as there was a progressive increase in the number of colonies after inoculation. The mean log CFU per swab was similar to that obtained by other authors 31,32 with the same inoculum size In the present in vivo study, comparison between the antifungal effects of silver nanoparticle solutions versus the standard antifungal agent (2% miconazole gel/suspension) showed that silver nanoparticles was superior to miconazole. The current results are in agreement with an in vitro study that used the same C. albicans (ATCC 90028) strain, the authors of which concluded that silver nanoparticles exhibited a more potent antifungal activity than fluconazole, an antifungal agent that is widely used against many fungal infections 17 .…”

“…The effective concentration of silver nanoparticles found in the present study was lower than that reported previously by other authors 16,17 . Compared with other U n c o r r e c t e d P r o f f metals, silver exhibits higher toxicity to microorganisms while it exhibits lower toxicity to mammalian cells [29][30][31][32][33] .…”

Antifungal Activities of R-135853, a Sordarin Derivative, in Experimental Candidiasis in Mice

“…This multiple interaction may explain the high degree of selectivity of this class of compounds between fungal and mammalian cells (12). Some pharmaceutical companies have reported that sordarin derivatives exhibit potent antifungal activities with relatively broad-spectrum activities in vitro and that some compounds exhibit good efficacies in vivo (2,7,15,16,17,25,26). We also synthesized sordarin derivatives from zofimarin, a sordarin-related natural product which was isolated from the fungus Zopfiella marina (32).…”

New Insights in Medical Mycology

“…GW-471558 ( Figure 4.4) is active against C. albicans, C. glabrata, and C. tropicalis including some isolates insensitive to fluconazole but inactive agaisnt C. parapsilosis, C. krusei, C. guilliermondii, and C. lusitaniae . GW-471552 and GW-471558 have significant therapeutic efficacy against vulvovaginal C. albicans infections (Martinez et al, 2001). R-35853, a sordarin derivative with a 1,4-oxazepane ring moiety ( Figure 4.4), has good in vitro activity against fluconazole-susceptible C. albicans strains, C. glabrata, C. tropicalis, and C. neoformans (Kamai et al, 2005).…”