Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction.

Détails

ID Serval
serval:BIB_A72A4B66EB19
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction.
Périodique
Nature
Auteur(s)
Nishikawa J.L., Boeszoermenyi A., Vale-Silva L.A., Torelli R., Posteraro B., Sohn Y.J., Ji F., Gelev V., Sanglard D., Sanguinetti M., Sadreyev R.I., Mukherjee G., Bhyravabhotla J., Buhrlage S.J., Gray N.S., Wagner G., Näär A.M., Arthanari H.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Statut éditorial
Publié
Date de publication
2016
Peer-reviewed
Oui
Volume
530
Numéro
7591
Pages
485-489
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
Animals, 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, Mice, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, 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
Pubmed
Web of science
Création de la notice
20/02/2016 16:17
Dernière modification de la notice
21/08/2019 5:14
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