Fludioxonil Induces Drk1, a Fungal Group III Hybrid Histidine Kinase, To Dephosphorylate Its Downstream Target, Ypd1

摘要: Novel antifungal drugs and targets are urgently needed. Group III hybrid histidine kinases (HHKs) represent an appealing new therapeutic drug target because they widely expressed in fungi but absent from humans. We investigated the mode of action utilized, effective fungicide fludioxonil. The acts HHK-dependent manner by constitutive activation HOG (high-osmolarity glycerol) pathway, its mechanism is poorly understood. Here, we report a that entails conversion HHK kinase into phosphatase. Drk1 (dimorphism-regulating kinase), which intracellular group fungal pathogen Blastomyces dermatitidis, Saccharomyces cerevisiae engendered sensitivity B. dermatitidis conferred upon S. In response to fludioxonil, behaved as phosphatase rather than kinase, leading dephosphorylation downstream target, Ypd1, yeast cell death. Aspartic acid residue 1140 receiver domain was required for vivo activity on Hog1 effect, indicating fidelity action. vitro assays with purified protein, intact demonstrated intrinsic activity, exhibited activity. However, fludioxonil failed induce dephosphorylate Ypd1. conclude treatment likely upstream triggers become phosphatase, dephosphorylates