AS2077715: A Novel Natural Product with Potent Activity against Trichophyton spp.

K. OHSUMI, T. MASAKI, I. NAKAMURA, M. YAMASHITA, S. TAKASE, M. WATANABE, A. FUJIE;

Author address: 

Astellas Pharma Inc., Ibaraki, Japan.

Abstract: 

Background: AS2077715 (AS), a novel antibiotic isolated from the fungus Capnodiaceae strain No.339855. We report here the antifungal activity against Trichophyton spp. and the mechanism of action of AS. Methods: MICs were determined by the microdilution method in 96-well culture plates in modified Sabouraud Dextrose (MSD) medium. Fungicidal activity was examined by time-kill assay. The test compounds were added to the MSD media 18 hours post-inoculation. Aliquots were removed, diluted, and plated to determine viable counts. In guinea pig models of tinea pedis, the test compounds were orally administered at 20 mg/kg once daily for 14 days. Fungal and mammal complex III inhibition was determined by ubiquinol-cytochrome c reductase assay with mitochondria fraction. Results: The MICs of AS against Trichophyton mentagrophytes FP2103 and T. rubrum FP596 were 0.10 and 0.10 μg/ml, respectively. In time-kill assays, terbinafine (1 μg/ml) showed fungicidal activity against T. mentagrophytes FP2103, with a reduction of >0.5 log10 cfu/ml over 24 hours; however, the same effect was observed within 6 hours with addition of AS (1 μg/ml). In a guinea pig model of tinea pedis, administration of AS produced a 2.1 log10-cfu/site reduction of T. mentagrophytes burden on pedal skin equal to terbinafine. IC50 values for AS inhibition of mitochondria complex III from T. mentagrophytes, rats, and humans were 1.9 nM, 1200 nM and 1000 nM, respectively. Conclusions: AS showed potent in vitro and in vivo antifungal activity against T. mentagrophytes, and selective inhibited activity of complex III of T. mentagrophytes. These results are suggestive of the potential use of this agent in treating tinea pedis.
2009

abstract No: 

F1-1498

Full conference title: 

49th Annual ICAAC
    • ICAAC 49th