title: Isolation, structure, and biological activities of Fellutamides C and D from an undescribed Metulocladosporiella (Chaetothyriales) using the genome-wide Candida albicans fitness test.
abstract: In a whole-cell mechanism of action (MOA)-based screening strategy for discovery of antifungal agents, Candida albicans was used, followed by testing of active extracts in the C. albicans fitness test (CaFT), which provides insight into the mechanism of action. A fermentation extract of an undescribed species of Metulocladosporiella that inhibited proteasome activity in a C. albicans fitness test was identified. The chemical genomic profile of the extract contained hypersensitivity of heterozygous deletion strains (strains that had one of the genes of the diploid genes knocked down) of genes represented by multiple subunits of the 25S proteasome. Two structurally related peptide aldehydes, named fellutamides C and D, were isolated from the extract. Fellutamides were active against C. albicans and Aspergillus fumigatus with MICs ranging from 4 to 16 μg/mL and against fungal proteasome (IC₅₀ 0.2 μg/mL). Both compounds showed proteasome activity against human tumor cell lines, potently inhibiting the growth of PC-3 prostate carcinoma cells, but not A549 lung carcinoma cells. In PC-3 cells compound treatment produced a G2M cell cycle block and induced apoptosis. Preliminary SAR studies indicated that the aldehyde group is critical for the antifungal activity and that the two hydroxy groups are quantitatively important for potency.
authors.affiliation: Department of Natural Products and Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors.forename: Deming
authors.initials: D
authors.lastname: Xu
authors.forename: John
authors.initials: J
authors.lastname: Ondeyka
authors.forename: Guy H
authors.initials: GH
authors.lastname: Harris
authors.forename: Deborah
authors.initials: D
authors.lastname: Zink
authors.forename: Jennifer Nielsen
authors.initials: JN
authors.lastname: Kahn
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Gerald
authors.initials: G
authors.lastname: Bills
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Platas
authors.forename: Wenxian
authors.initials: W
authors.lastname: Wang
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: Paul
authors.initials: P
authors.lastname: Liberator
authors.forename: Terry
authors.initials: T
authors.lastname: Roemer
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001203:Ascomycota / Q000737:chemistry*; D002176:Candida albicans / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D009842:Oligopeptides; C562120:fellutamide C; C562121:fellutamide D