Antifungal Spectrum, In Vivo Efficacy, and Structure鈥揂ctivity Relationship of Ilicicolin H

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• 作者：Sheo B. Singh ; Weiguo Liu ; Xiaohua Li ; Tom Chen ; Ali Shafiee ; Deborah Card ; George Abruzzo ; Amy Flattery ; Charles Gill ; John R. Thompson ; Mark Rosenbach ; Sarah Dreikorn ; Viktor Hornak ; Maria Meinz ; Myra Kurtz ; Rosemarie Kelly ; Janet C. Onishi
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：3
• 期：10
• 页码：814-817
• 全文大小：235K
• 年卷期：v.3,no.10(October 11, 2012)
• ISSN：1948-5875

文摘

Ilicicolin H is a polyketide鈥攏onribosomal peptide synthase (NRPS)鈥攏atural product isolated from Gliocadium roseum, which exhibits potent and broad spectrum antifungal activity, with sub-渭g/mL MICs against Candida spp., Aspergillus fumigatus, and Cryptococcus spp. It showed a novel mode of action, potent inhibition (IC₅₀ = 2鈥? ng/mL) of the mitochondrial cytochrome bc1 reductase, and over 1000-fold selectivity relative to rat liver cytochrome bc1 reductase. Ilicicolin H exhibited in vivo efficacy in murine models of Candida albicans and Cryptococcus neoformans infections, but efficacy may have been limited by high plasma protein binding. Systematic structural modification of ilicicolin H was undertaken to understand the structural requirement for the antifungal activity. The details of the biological activity of ilicicolin H and structural modification of some of the key parts of the molecule and resulting activity of the derivatives are discussed. These data suggest that the 尾-keto group is critical for the antifungal activity.

Keywords:

ilicicolin H; Gliocadium roseum; antifungal activity; broad spectrum; cytochrome bc1 reductase inhibitor; in vivo efficacy