Accelerating the discovery of biologically active small molecules using a high-throughput yeast halo assay

J Nat Prod. 2007 Mar;70(3):383-90. doi: 10.1021/np060555t. Epub 2007 Feb 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antifungal Agents / pharmacology*
  • Combinatorial Chemistry Techniques
  • Drug Evaluation, Preclinical*
  • Guanidine / analogs & derivatives*
  • Guanidine / pharmacology
  • Models, Biological*
  • Molecular Structure
  • Porifera / chemistry*
  • Saccharomyces cerevisiae / metabolism*
  • Spiro Compounds / pharmacology*

Substances

  • Antifungal Agents
  • Spiro Compounds
  • crambescidin 800
  • Guanidine