A compendium of genome-wide drug hypersensitivity screens provides insight into compound mode-of-action.
Ainslie B. Parsons (1), Andres Lopez (1), Renee Brost (1), David Williams (2), Raymond Anderson (2), Timothy Hughes (1), Charles Boone (1)
(1) Best Institute, University of Toronto, 112 College St, Toronto, On, M5G 1L6, Canada; (2) Department of Chemistry, University of British Columbia, Vancouver, Canada
Bioactive compounds can be valuable research tools and drug leads, but it is often difficult to identify their cellular targets. Here we present a large compendium of 'chemical-genetic interaction' profiles where the complete collection of yeast viable haploid deletion mutants are tested for hypersensitivity to anti-fungal compounds using parallel fitness tests and a microarray-based readout. Our compendium currently contains over 60 diverse compounds and natural product extracts, including a number of human therapeutics. Hierarchical clustering of our dataset associates compounds of similar mode-of-action and reveals insight into the cellular pathways affected by the compounds. We are now applying this compendium approach to identify the targets of unknown compounds. In particular, Papuamide B, a large cyclic lipopeptide with potent anti-fungal activity, is intriguing because our analysis suggests it may function similarly to alamethicin, a compound that compromises cell membrane integrity. We have isolated PapB resistant mutants and identified one as a cho1 mutant. CHO1 encodes a non-essential enzyme required for the synthesis of phosphatidylserine (PS), one of four major phospholipids found in the yeast cell membrane. Further analysis is suggestive of an interaction between PapB and PS and we are currently examining whether PapB may be entering the cell via PS and then acting on an intracellular target or if PapB could be exerting its effect directly through PS.