Antifungal spectrum, in vivo efficacy, and structure-activity relationship of ilicicolin h.

Abstract

Ilicicolin H is a polyketide-nonribosomal peptide synthase (NRPS)-natural product isolated from Gliocadium roseum, which exhibits potent and broad spectrum antifungal activity, with sub-μg/mL MICs against Candida spp., Aspergillus fumigatus, and Cryptococcus spp. It showed a novel mode of action, potent inhibition (IC50 = 2-3 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 β-keto group is critical for the antifungal activity.

• Authors: 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
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 3 Issue 10 Pg. 814-7 (Oct 11 2012) ISSN: 1948-5875 [Print] United States
• PMID: 24900384 (Publication Type: Journal Article)