Chemical-genetic approaches for exploring the mode of action of natural products.
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 approximately 5000 viable haploid and homozygous diploid deletion mutants and the complete set of approximately 6000 heterozygous deletion mutants, containing the set of approximately 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 approximately 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 approximately 6000 yeast genes.
Lopez
Andres
A
Banting and Best Department of Medical Research and Department of Medical Genetics and Microbiology, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Canada.
Parsons
Ainslie B
AB
Nislow
Corey
C
Giaever
Guri
G
Boone
Charles
C
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D016000:Cluster Analysis; D015195:Drug Design; D017353:Gene Deletion; D018628:Gene Dosage; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D053263:Gene Regulatory Networks; D005818:Genetic Engineering; D023281:Genomics; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013678:Technology, Pharmaceutical
D000935:Antifungal Agents; D001688:Biological Products