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

Abstract

The activities of R-135853, a novel sordarin derivative that possesses a 1,4-oxazepane ring moiety, were evaluated in vitro and in vivo. R-135853 exhibited potent in vitro activities against Candida albicans (fluconazole-susceptible strains), Candida glabrata, Candida tropicalis, and Cryptococcus neoformans, with MICs at which 90% of isolates were inhibited of 0.03, 1, 0.5, and 0.5 g/ml, respectively. R-135853 also exhibited potent activities against fluconazole-susceptible dose-dependent and fluconazole-resistant strains of C. albicans, with MICs ranging from 0.03 to 0.06 g/ml. However, R-135853 exhibited weak or no activity against Candida parapsilosis, Candida krusei, and Aspergillus spp. R-135853 exhibited dose-dependent efficacy against experimental murine hematogenous candidiasis induced by C. albicans when it was administered by both the subcutaneous and the oral routes and reduced viable cell counts in the kidneys significantly when it was administered at 50 mg/kg of body weight/dose (administration three times a day). In this model, R-135853 also exhibited dose-dependent efficacy by single oral administration. Subcutaneous administration of R-135853 exhibited dose-dependent efficacy against experimental murine esophageal candidiasis induced by fluconazoleresistant C. albicans, against which fluconazole at 50 mg/kg/dose was ineffective, and reduced viable cell counts in the esophagus significantly when it was administered at 10 and 50 mg/kg/dose. R-135853 eradicated C. albicans from the esophagi of one and four of five mice when it was administered at 10 and 50 mg/kg/dose, respectively. These results suggest that R-135853 is promising for the treatment of disseminated or mucosal candidiasis, including fluconazole-refractory infections.

Emerging drugs and vaccines for Candidemia

“…Sordarin is a natural product isolated from Sordaria araneosa . Since its discovery, several structurally related compounds have been isolated and/or developed . Sordarin, and its derivatives, bind to elongation factor 2 (eEF2), stabilising the eEF2/ribosome complex via a likely additional interaction with ribosomal subunit protein (rpP0), and preventing the final step of translocation in protein synthesis .…”

“…Since its discovery, several structurally related compounds have been isolated and/or developed . Sordarin, and its derivatives, bind to elongation factor 2 (eEF2), stabilising the eEF2/ribosome complex via a likely additional interaction with ribosomal subunit protein (rpP0), and preventing the final step of translocation in protein synthesis . Despite eEF2 being highly conserved among eukaryotes, sordarin and its derivatives only interact with a very specific region of eEF2, which is unique to fungal species, particularly Candida spp .…”

“…Despite eEF2 being highly conserved among eukaryotes, sordarin and its derivatives only interact with a very specific region of eEF2, which is unique to fungal species, particularly Candida spp . Sordarin derivatives have been evaluated in murine models of disseminated candidiasis . While these agents have not been tested in humans to date, low cytotoxicity has been reported for some compounds …”

Recent Advances in Antifungal Agents

“…These observations suggest a highly specific binding of the sordarins that can also explain the inhibition of the fungal but not mammalian protein synthesis. In addition they were active against the C. neoformans and P. carinii strains in murine model [96,97] but showed low activity against A. fumigatus strains [98]. The selective inhibition of the eEF-2 gives an opportunity to design antifungal agents of unique mechanism of action.…”

New Insights in Medical Mycology

“…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). MICs of R-135853 against dose-dependent fluconazole-susceptible and fluconazole-resistant strains of C. albicans are 0.03-0.06 µg/mL.…”