F1-1183. Antifungal Activity of a Novel Orally Active Sordarin Derivative, FR290581
Session: Poster Session: New Anti-Fungal Agents
Sunday, October 26, 2008: 12:00 AM
Room: Hall C
Background: The antifungal natural product sordarin inhibits protein synthesis by a mechanism involving selective targeting of translation elongation factor 2 in fungi. Because of the weak antifungal activity and poor pharmacokinetic profile of sordarin itself, however, in vivo antifungal activity is negligible. We have discovered a novel derivative, FR290581 (FR), by chemical modification of sordaricin, the aglycone unit of sordarin. We report herein the superior antifungal activities of FR in vitro and in vivo. Methods: In vitro antifungal activity against pathogenic fungi was evaluated according to CLSI M27-A2, M38-A, and using animal serum. Therapeutic activity against Candida albicans (C.a)- infected ICR mouse models and Pneumocystis jirovecii (P.j)-infected SCID mouse model was evaluated orally. Results: FR displayed potent in vitro activity against C.a, C. tropicalis, and C. kefyr, which was comparable to fluconazole (FLCZ), but showed only negligible activity against C. parapsilosis, C. neoformans, and A. fumigatus. In a mouse systemic candidiasis model of C.a, FR had a comparable survival effect to FLCZ and had fungicidal activity against kidney fungal burden whereas FLCZ had only a fungistatic effect. In mouse oropharyngeal candidiasis, FR had a similar mycological effect in tongue as compared with FLCZ. FR also had more potent in vivo activities against P.j as compared with sulfamethoxazole-trimethoprim (ST). (see table) Conclusions: FR had potent in vivo activity against C.a and P.j compared with existing drugs. The antifungal profile of FR suggests it may be useful for AIDS patients.
Number of P.j cysts and histological changes in mouse lung
Group No. of cysts (x 103)Pneumonia (positive)Mononuclear cell infiltration
Control-1187.5±628.98/8impossible for analysis
FR5mg/kg0.6±1.6*0/82/8
20mg/kg0*0/81/8
ST120mg/kg1.1±1.9*0/88/8
*: significantly difference from the control (p<0.01)
David Barrett1, Fumiaki Ikeda2, Katsuyuki Maki3, Kazuo Hatano, PhD4, Kazuyuki Hatakenaka1, Kenichi Washizuka1, Masaki Tomishima1, Satoru Matsumoto5, Shinobu Takeda3, Tadaatsu Hanadate1 and  S. Matsumoto, None., (1)Astellas Pharma. Inc, (2)Mitsubishi Chemical Medience Corporation, (3)Astellas Pharma Inc., (4)Astellas Pharma Inc., Osaka, Japan, (5)Astellas Pharma. Inc, Osaka, Japan


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