ArticleAntimicrobial agents and chemotherapy2017
Fludioxonil Induces Drk1, a Fungal Group III Hybrid Histidine Kinase, To Dephosphorylate Its Downstream Target, Ypd1.
Article in Antimicrobial agents and chemotherapy, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 46 citations in OpenAlex.
- Conformational diversity in poly-HAMP arrays and its implications for signal transduction.Protein science : a publication of the Protein Society · 2026Article
- Hybrid histidine kinases and antifungal warfare in thermal dimorphic fungi.Antimicrobial agents and chemotherapy · 2026Review
- Porphyrin-Linked Antifungal Nanocarrier Promotes Plant Growth via UV RESISTANCE LOCUS 8-Mediated Light Signalling Activation.Plant biotechnology journal · 2026Article
- Hybrid histidine kinases shape the architecture of the high osmolarity glycerol (HOG) pathway: from Saccharomyces cerevisiae to the priority pathogen Aspergillus fumigatus and other filamentous fungi.FEMS microbiology reviews · 2026Review
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- Proteomic Changes inJournal of proteome research · 2025Article
- The N-terminus of themBio · 2024Article
- Common virulence factors betweenCurrent research in microbial sciences · 2024Review
- Polypeptides TargetingJournal of fungi (Basel, Switzerland) · 2023Article
- Induced Expression ofMicroorganisms · 2023Article
- The Transcription Factor CsAtf1 Negatively Regulates the Cytochrome P450 GeneJournal of fungi (Basel, Switzerland) · 2022Article
- Cell Wall Integrity and Its Industrial Applications in Filamentous Fungi.Journal of fungi (Basel, Switzerland) · 2022Review
- The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic FungusJournal of fungi (Basel, Switzerland) · 2021Article
- Predicted Functional and Structural Diversity of Receiver Domains in Fungal Two-Component Regulatory Systems.mSphere · 2021Article
- Drk1, a Dimorphism Histidine Kinase, Contributes to Morphology, Virulence, and Stress Adaptation inJournal of fungi (Basel, Switzerland) · 2021Article
- A Radical Reimagining of Fungal Two-Component Regulatory Systems.Trends in microbiology · 2021Review
- Distinct role of HAMP and HAMP-like linker domains in regulating the activity of Hik1p, a hybrid histidine kinase 3 from Magnaporthe oryzae.Molecular genetics and genomics : MGG · 2021Article
- Article
- The Molecular Mechanism of Fludioxonil Action Is Different to Osmotic Stress Sensing.Journal of fungi (Basel, Switzerland) · 2021Article
- Non-Target Site Mechanisms of Fungicide Resistance in Crop Pathogens: A Review.Microorganisms · 2021Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Novel antifungal drugs and targets are urgently needed. Group III hybrid histidine kinases (HHKs) represent an appealing new therapeutic drug target because they are widely expressed in fungi but absent from humans. We investigated the mode of action of the widely utilized, effective fungicide fludioxonil. The drug acts in an HHK-dependent manner by constitutive activation of the HOG (high-osmolarity glycerol) pathway, but its mechanism of action is poorly understood. Here, we report a new mode of drug action that entails conversion of the HHK from a kinase into a phosphatase. We expressed Drk1 (dimorphism-regulating kinase), which is an intracellular group III HHK from the fungal pathogen Blastomyces dermatitidis, in Saccharomyces cerevisiae Drk1 engendered drug sensitivity in B. dermatitidis and conferred sensitivity upon S. cerevisiae In response to fludioxonil, Drk1 behaved as a phosphatase rather than as a kinase, leading to dephosphorylation of its downstream target, Ypd1, constitutive activation of the HOG pathway, and yeast cell death. Aspartic acid residue 1140 in the Drk1 receiver domain was required for in vivo phosphatase activity on Ypd1, and Hog1 was required for drug effect, indicating fidelity in HHK-dependent drug action. In in vitro assays with purified protein, intact Drk1 demonstrated intrinsic kinase activity, and the Drk1 receiver domain exhibited intrinsic phosphatase activity. However, fludioxonil failed to induce intact Drk1 to dephosphorylate Ypd1. We conclude that fludioxonil treatment in vivo likely acts on an upstream target that triggers HHK to become a phosphatase, which dephosphorylates its downstream target, Ypd1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.