title: 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.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Tom
authors.initials: T
authors.lastname: Chen
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ali
authors.initials: A
authors.lastname: Shafiee
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: Card
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: George
authors.initials: G
authors.lastname: Abruzzo
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Flattery
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Gill
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Rosenbach
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dreikorn
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Viktor
authors.initials: V
authors.lastname: Hornak
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Meinz
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Myra
authors.initials: M
authors.lastname: Kurtz
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Kelly
authors.affiliation: Departments Medicinal Chemistry and Infectious Diseases, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Janet C
authors.initials: JC
authors.lastname: Onishi
keywords: Gliocadium roseum; antifungal activity; broad spectrum; cytochrome bc1 reductase inhibitor; ilicicolin H; in vivo efficacy