title: Accelerating the discovery of biologically active small molecules using a high-throughput yeast halo assay.
abstract: The budding yeast Saccharomyces cerevisiae, a powerful model system for the study of basic eukaryotic cell biology, has been used increasingly as a screening tool for the identification of bioactive small molecules. We have developed a novel yeast toxicity screen that is easily automated and compatible with high-throughput screening robotics. The new screen is quantitative and allows inhibitory potencies to be determined, since the diffusion of the sample provides a concentration gradient and a corresponding toxicity halo. The efficacy of this new screen was illustrated by testing materials including 3104 compounds from the NCI libraries, 167 marine sponge crude extracts, and 149 crude marine-derived fungal extracts. There were 46 active compounds among the NCI set. One very active extract was selected for bioactivity-guided fractionation, resulting in the identification of crambescidin 800 as a potent antifungal agent.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Nadine C
authors.initials: NC
authors.lastname: Gassner
authors.forename: Craig M
authors.initials: CM
authors.lastname: Tamble
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Bock
authors.forename: Naomi
authors.initials: N
authors.lastname: Cotton
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: White
authors.forename: Karen
authors.initials: K
authors.lastname: Tenney
authors.forename: Robert P
authors.initials: RP
authors.lastname: St Onge
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Proctor
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Davis
authors.forename: Phillip
authors.initials: P
authors.lastname: Crews
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
authors.forename: R Scott
authors.initials: RS
authors.lastname: Lokey
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D019791:Guanidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008954:Models, Biological; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D013141:Spiro Compounds; C490355:crambescidin 800; D019791:Guanidine