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 (IC
50 = 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