The possible mechanism of action of ciclopirox olamine in the yeast Saccharomyces cerevisiae

Ciclopirox olamine is a synthetic antifungal agent with a high affinity for trivalent metal cations. Ciclopirox olamine can be used to synchronize mammalian cells, but its mechanism of action is not understood well. In this study, we investigated the effect of ciclopirox olamine in yeast cells and used a genetic approach to identify potential ciclopirox olamine targets in yeast. Wild type strains of the yeast Saccharomyces cerevisiae were weakly sensitive to ciclopirox olamine, but high concentrations of the drug arrested their growth at many different stages. MMS-mutagenized yeast clones were screened for increased sensitivity to ciclopirox olamine. Fourteen mutants, cos101-cos114, were identified and characterized. The targets of ciclopirox olamine in S. cerevisiae appear to include multiple proteins that participate in various components of cellular metabolism, including DNA replication, DNA repair, and cellular transport. Three genes were cloned: a Fe/Cu reductase (FRE1/COS107), an oxidative stress response gene (YAP1/COS110), and a gene involved in signal transduction (YBR203W/COS111). These results suggest that CPO inhibits multiple aspects of cell growth and metabolism, possibly via multiple targets.