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| Status |
Public on Dec 15, 2015 |
| Title |
Inhibiting Fungal Multidrug Resistance by Disrupting an Activator-Mediator Interaction With the Small Molecule iKIX1 |
| Organisms |
Saccharomyces cerevisiae; Nakaseomyces glabratus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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. We previously identified an activator-targeted ~85 amino acid three-helix bundle KIX domain in the human MED15 Mediator subunit that is structurally conserved in Gal11 Mediator subunits in fungi. The Gal11 KIX domain is engaged by pleiotropic drug resistance transcription factor (Pdr1) orthologues, key regulators of the multidrug resistance (MDR) pathway in S. cerevisiae and in the clinically important human pathogen Candida glabrata. Drug-resistant clinical isolates of C. glabrata most commonly harbour point mutations in Pdr1 that render it constitutively active, suggesting that this transcriptional activation pathway may represent a lynchpin in C. glabrata MDR. We have now carried out 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 in both S. cerevisiae and C. glabrata and re-sensitizes drug-resistant C. glabrata to effective azole antifungal concentrations in vitro and in animal models for disseminated and urinary tract C. glabrata infection.
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| Overall design |
Samples are generated in triplicate for four conditions (DMSO/vehicle-treated, iKIX1-treated, DMSO/vehicle and ketoconazole-treated. and iKIX1-ketoconazole treated) in both Saccharomyces cerevisiae and Candida glabrata
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| Contributor(s) |
Nishikawa JL, Naar AM, Ji F, Sadreyev RI |
| Citation(s) |
26886795 |
| |
| Submission date |
Oct 26, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Joy Luz Nishikawa |
| Organization name |
Massachusetts General Hospital / Harvard Medical School
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| Department |
Cancer Center / Cell Biology
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| Lab |
Anders Naar
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| Street address |
Bldg 149, 13th Street
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| City |
Charlestown |
| State/province |
MA |
| ZIP/Postal code |
02129 |
| Country |
USA |
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| Platforms (2) |
| GPL17342 |
Illumina HiSeq 2500 (Saccharomyces cerevisiae) |
| GPL21066 |
Illumina HiSeq 2500 (Candida glabrata) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA299815 |
| SRA |
SRP065276 |
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