Clotrimazole-Induced Oxidative Stress Triggers Novel Yeast Pkc1-Independent Cell Wall Integrity MAPK Pathway Circuitry

Azoles are one of the most widely used drugs to treat fungal infections. To further understand response azoles, we analyzed MAPK circuitry model yeast Saccharomyces cerevisiae that operates under treatment with these antifungals. Imidazoles, and particularly clotrimazole, trigger deeper changes in phosphorylation than triazoles, involving a reduction signaling through mating pathway activation MAPKs Hog1 Slt2 from High-Osmolarity Glycerol (HOG) Cell Wall Integrity (CWI) pathways, respectively. Clotrimazole leads actin aggregation, mitochondrial alteration, oxidative stress, which is essential not only for both MAPKs, but also appearance low-mobility form caused by additional occurring at conserved TEY motif. Clotrimazole-induced ROS production linked Tpk3-mediated PKA activity. Resistance clotrimazole depends on HOG CWI-pathway-mediated stress responses. However, Pkc1 other proteins acting upstream critical module, suggesting novel rewiring CWI pathway. We show strong impact azole species.