title: 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 microg/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 mug/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 fluconazole-resistant 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.
authors.affiliation: Biological Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. ykamai@sankyo.co.jp
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kamai
authors.forename: Masayo
authors.initials: M
authors.lastname: Kakuta
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukuoka
authors.forename: Shogo
authors.initials: S
authors.lastname: Kuwahara
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002175:Candida / Q000145:classification / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D025141:Drug Resistance, Fungal; D004935:Esophageal Diseases / Q000188:drug therapy / Q000382:microbiology; D015725:Fluconazole / Q000494:pharmacology; D016469:Fungemia / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D007192:Indenes; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D001381:Azepines; D001952:Bridged-Ring Compounds; D007192:Indenes; C496526:R 135853; C003329:sordarin; D015725:Fluconazole