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

Basic Information

ID: ALA2177002

Journal: ACS Med Chem Lett

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

Authors: Singh SB, Liu W, Li X, Chen T, Shafiee A, Card D, Abruzzo G, Flattery A, Gill C, Thompson JR, Rosenbach M, Dreikorn S, Hornak V, Meinz M, Kurtz M, Kelly R, Onishi JC.

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.

CiteXplore: 24900384

DOI: 10.1021/ml300173e

Patent ID: ┄

Associated Items: Associated Bioactivities Associated Assays Associated Compounds Associated Targets