Chemical-genetic approaches for exploring the mode of action of natural products

  • Andres Lopez
  • Ainslie B. Parsons
  • Corey Nislow
  • Guri Giaever
  • Charles Boone
Part of the Progress in Drug Research book series (PDR, volume 66)


Determining the mode of action of bioactive compounds, including natural products, is a central problem in chemical biology. Because many genes are conserved from the yeast Saccharomyces cerevisiae to humans and a number of powerful genomics tools and methodologies have been developed for this model system, yeast is making a major contribution to the field of chemical genetics. The set of barcoded yeast deletion mutants, including the set of ∼5000 viable haploid and homozygous diploid deletion mutants and the complete set of ∼6000 heterozygous deletion mutants, containing the set of ∼1000 essential genes, are proving highly informative for identifying chemical-genetic interactions and deciphering compound mode of action. Gene deletions that render cells hypersensitive to a specific drug identify pathways that buffer the cell against the toxic effects of the drug and thereby provide clues about both gene and compound function. Moreover, compounds that show similar chemical- genetic profiles often perturb similar target pathways. Gene dosage can be exploited to discover connections between compounds and their targets. For example, haploinsufficiency profiling of an antifungal compound, in which the set of ∼6000 heterozygous diploid deletion mutants are scored for hypersensitivity to a compound, may identify the target directly. Creating deletion mutant collections in other fungal species, including the major human fungal pathogen Candida albicans, will expand our chemical genomics tool set, allowing us to screen for antifungal lead drugs directly. The yeast deletion mutant collection is also being exploited to map large-scale genetic interaction data obtained from genome-wide synthetic lethal screens and the integration of this data with chemical genetic data should provide a powerful system for linking compounds to their target pathway. Extensive application of chemical genetics in yeast has the potential to develop a small molecule inhibitor for the majority of all ∼6000 yeast genes.


Genetic Interaction ABIETIC Acid ARTEMISINIC Acid Cell Wall Organization FENPROPI Morph 


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Copyright information

© Birkhäuser Verlag, Basel (Switzerland) 2008

Authors and Affiliations

  • Andres Lopez
    • 1
  • Ainslie B. Parsons
    • 1
  • Corey Nislow
    • 1
  • Guri Giaever
    • 1
    • 2
  • Charles Boone
    • 1
  1. 1.Banting and Best Department of Medical Research and Department of Medical Genetics and Microbiology, Terrence Donnelly Centre for Cellular and Biomolecular ResearchUniversity of TorontoTorontoCanada
  2. 2.Department of Pharmaceutical Sciences and Department of Molecular and Medical Genetics, Terrence Donnelly Centre for Cellular and Biomolecular ResearchUniversity of TorontoTorontoCanada

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