Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction
| Autor: | Joy L. Nishikawa, Dominique Sanglard, Anders M. Näär, Riccardo Torelli, Luís A. Vale-Silva, Maurizio Sanguinetti, Brunella Posteraro, Haribabu Arthanari, Andras Boeszoermenyi, Ruslan I. Sadreyev, Jayaram Bhyravabhotla, Goutam Dev Mukherjee, Gerhard Wagner, Fei Ji, Sara J. Buhrlage, Nathanael S. Gray, Yoo-Jin Sohn, Vladimir Gelev |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Transcriptional Activation 0301 basic medicine Antifungal Agents Saccharomyces cerevisiae Proteins 030106 microbiology Candida glabrata Biology Article Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA Microbiology Fungal Proteins Mice 03 medical and health sciences Mediator Drug Resistance Fungal Transcription (biology) Drug Resistance Multiple Fungal Gene Expression Regulation Fungal Animals Fluconazole Nuclear Magnetic Resonance Biomolecular Transcription factor Regulation of gene expression Fungal protein Binding Sites Mediator Complex Multidisciplinary Activator (genetics) Eukaryotic transcription Candidiasis Thiourea Antifungal Agents/pharmacology Binding Sites/drug effects Candida glabrata/drug effects Candida glabrata/genetics Candidiasis/drug therapy Candidiasis/microbiology DNA-Binding Proteins/genetics DNA-Binding Proteins/metabolism Drug Resistance Fungal/drug effects Drug Resistance Multiple Fungal/drug effects Fluconazole/pharmacology Fungal Proteins/metabolism Gene Expression Regulation Fungal/drug effects Hydrazines/pharmacokinetics Hydrazines/pharmacology Ketoconazole/pharmacology Mediator Complex/chemistry Mediator Complex/metabolism Protein Binding/drug effects Protein Structure Tertiary Saccharomyces cerevisiae Proteins/chemistry Saccharomyces cerevisiae Proteins/genetics Thiourea/analogs & derivatives Thiourea/pharmacokinetics Trans-Activators/chemistry Trans-Activators/metabolism Transcription Factors/genetics Transcription Factors/metabolism Transcriptional Activation/drug effects Up-Regulation/drug effects biology.organism_classification Up-Regulation 3. Good health DNA-Binding Proteins Hydrazines Ketoconazole 030104 developmental biology Trans-Activators Protein Binding Transcription Factors |
| Zdroj: | Nature Europe PubMed Central Nature, vol. 530, no. 7591, pp. 485-489 |
| Popis: | Eukaryotic transcription activators stimulate the expression of specific sets of target genes through recruitment of co-activators such as the RNA polymerase II-interacting Mediator complex. Aberrant function of transcription activators has been implicated in several diseases. However, therapeutic targeting efforts have been hampered by a lack of detailed molecular knowledge of the mechanisms of gene activation by disease-associated transcription activators. We previously identified an activator-targeted three-helix bundle KIX domain in the human MED15 Mediator subunit that is structurally conserved in Gal11/Med15 Mediator subunits in fungi. The Gal11/Med15 KIX domain engages pleiotropic drug resistance transcription factor (Pdr1) orthologues, which are key regulators of the multidrug resistance pathway in Saccharomyces cerevisiae and in the clinically important human pathogen Candida glabrata. The prevalence of C. glabrata is rising, partly owing to its low intrinsic susceptibility to azoles, the most widely used antifungal agent. Drug-resistant clinical isolates of C. glabrata most commonly contain point mutations in Pdr1 that render it constitutively active, suggesting that this transcriptional activation pathway represents a linchpin in C. glabrata multidrug resistance. Here we perform sequential biochemical and in vivo high-throughput screens to identify small-molecule inhibitors of the interaction of the C. glabrata Pdr1 activation domain with the C. glabrata Gal11A KIX domain. The lead compound (iKIX1) inhibits Pdr1-dependent gene activation and re-sensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models for disseminated and urinary tract C. glabrata infection. Determining the NMR structure of the C. glabrata Gal11A KIX domain provides a detailed understanding of the molecular mechanism of Pdr1 gene activation and multidrug resistance inhibition by iKIX1. We have demonstrated the feasibility of small-molecule targeting of a transcription factor-binding site in Mediator as a novel therapeutic strategy in fungal infectious disease. |
| Databáze: | OpenAIRE |
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