Chemogenetic fingerprinting by analysis of cellular growth dynamics

Using the model organism Saccharomyces cerevisiae we here report that resolving cellular growth dynamics into its individual components, growth lag, growth rate and growth efficiency, increases the predictive power of chemogenetic screens. Both in terms of drug-drug and gene-drug interactions did the individual growth variables capture distinct and only partially overlapping aspects of cell physiology. In fact, the impact on cellular growth dynamics represented functionally distinct chemical fingerprints.Our findings suggest that the resolution and quantification of all facets of growth increases the informational and interpretational output of chemogenetic screening. Hence, by facilitating a physiologically more complete analysis of gene-drug and drug-drug interactions the here reported results may simplify the assignment of mode-of-action to orphan bioactive compounds.Specifying on- and off-target effects of drugs and biocides constitutes a central goal in pharmacology, ecotoxicology and chemical biology. Drugs are also used as potent inhibitors generating specific perturbations in systems biology. The overall chemotoxicity of compounds is typically measured as the growth reducing impact on organisms. Mode-of-action information of a drug can be obtained by quantifying changes in fitness of genome-wide collections of knockout strains [1-5]. Knockouts that render cells sensitive to a drug identify pathways that buffer the cell against the chemical perturbation, thereby providing clues about its mechanism of toxicity. Moreover, compounds with similar biological effects have similar chemogenetic profiles [6-8]. Thus, analysis of a compendium of chemical genetic profiles facilitates the identification of bioactive compounds with similar biological effects and the tentative assignment of biological targets to novel drugs. This approach has been successfully applied using both yeast [1-5] and bacteria [9,10]. In genome-wide chemogenetic approaches the fitness of knockout