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

Details

Serval ID
serval:BIB_A72A4B66EB19
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction.
Journal
Nature
Author(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
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
530
Number
7591
Pages
485-489
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
Keywords
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
Create date
20/02/2016 16:17
Last modification date
21/08/2019 5:14
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