Accelerating the discovery of biologically active small molecules using a high-throughput yeast halo assay.
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.
Gassner
Nadine C
NC
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.
Tamble
Craig M
CM
Bock
Jonathan E
JE
Cotton
Naomi
N
White
Kimberly N
KN
Tenney
Karen
K
St Onge
Robert P
RP
Proctor
Michael J
MJ
Giaever
Guri
G
Nislow
Corey
C
Davis
Ronald W
RW
Crews
Phillip
P
Holman
Theodore R
TR
Lokey
R Scott
RS
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*
D000935:Antifungal Agents; D013141:Spiro Compounds; C490355:crambescidin 800; D019791:Guanidine