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BioAssay: AID 2007

Summary of Broad Institute MLPCN Reversing Antifungal Drug Resistance Project.

Acquired drug resistance by medically relevant microorganisms poses a grave threat to human health and has enormous economic consequences. Fungal pathogens pose a particular challenge because they are eukaryotes and share many of the same mechanisms that support the growth and survival of the cells comprising their human hosts. The number of drug classes that have distinct targets in fungi is more ..
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 Tested Compounds
 Tested Compounds
All(3)
 
 
Probe(3)
 
 
Active(3)
 
 
 Tested Substances
 Tested Substances
All(3)
 
 
Probe(3)
 
 
Active(3)
 
 
AID: 2007
Data Source: Broad Institute (2037-01_INHIBITORS)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-10-22
Modify Date: 2011-10-12

Data Table ( Complete ):           View Active Data    View All Data
Target
BioActive Compounds: Chemical Probe: 3    Active: 3
Related Experiments
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AIDNameTypeComment
1979Fluorescence Cell-Based Primary HTS of C.albicans growth in the presence of Fluconazole and compoundScreeningdepositor-specified cross reference: 302509 hts compounds at singlepoint in Antifungal Primary measuring activity set 1
2327Fluorescence Cell-Based Secondary Assay for toxicity in mammalian fibroblastsConfirmatorydepositor-specified cross reference: 1837 cherrypick compounds at dose in Antifungal Secondary - fibroblasts measuring activity set 1
2387Fluorescence Cell-Based Secondary Assay to Measure Toxicity of Compounds Not in the Presence of FluconazoleConfirmatorydepositor-specified cross reference: 344 cherrypick compounds at dose in AF Secondary - No Fluconazole measuring activity set 1
2388Luminesence Cell-Based Secondary Assay to Identify Inhibitors of CalcineurinConfirmatorydepositor-specified cross reference: 344 cherrypick compounds at dose in AF Secondary - Calcineurin Yeast Reporter measuring activity set
2400Luminesence Cell-Based Secondary Assay to Identify Inhibitors of Hsp90Confirmatorydepositor-specified cross reference: 344 cherrypick compounds at dose in AF Secondary - Hsp90 Yeast Reporter measuring activity set 1
2423Fluorescence Cell-Based Secondary Assay to Identify Inhibitors of Resistant C. albicans Growth in the Presence of FluconazoleConfirmatorydepositor-specified cross reference: 1838 cherrypick compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 1
2467Fluorescence Cell-Based Retest of C. albicans Growth in the Presence of FluconazoleConfirmatorydepositor-specified cross reference: 1838 cherrypick compounds at dose in Antifungal Primary measuring activity set 1
434923Fluorescence Cell-Based Secondary Assay for Toxicity in Mammalian FibroblastsConfirmatorydepositor-specified cross reference: 29 drypowder compounds at dose in Antifungal Secondary - fibroblasts measuring activity set 1
434930Fluorescence Cell-Based Retest of C. albicans growth in the presence of fluconazole and compoundConfirmatorydepositor-specified cross reference: 29 drypowder compounds at dose in Antifungal Primary measuring activity set 1
434935Fluorescence Cell-Based Secondary Assay of Resistant C. albicans Growth in the Presence of FluconazoleConfirmatorydepositor-specified cross reference: 29 drypowder compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 1
434938Luminescence Cell-Based Secondary Assay to Identify Inhibitors of Hsp90Confirmatorydepositor-specified cross reference: 29 drypowder compounds at dose in AF Secondary - Hsp90 Yeast Reporter measuring activity set 1
434945Fluorescence Cell-Based Secondary Assay to Identify Inhibitors of CalcineurinConfirmatorydepositor-specified cross reference: 29 drypowder compounds at dose in AF Secondary - Calcineurin Yeast Reporter measuring activity set 1
434946Fluorescence Cell-Based Secondary Assay to Measure Toxicity of Compounds Not in the Presence of Fluconazole.Confirmatorydepositor-specified cross reference: 29 drypowder compounds at dose in AF Secondary - No Fluconazole measuring activity set 1
488802Antifungal Drug Resistance - Single Agent Toxicity Measured in Microorganism System Using Plate Reader - 2037-07_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: 44 drypowder compounds at dose in AF Secondary - No Fluconazole measuring activity set 6
488807Antifungal Drug Resistance - Resistant Strain Measured in Microorganism System Using Plate Reader - 2037-02_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: 44 drypowder compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 8
488809Antifungal Drug Resistance - Mammalian Cell Toxicity Measured in Cell-Based System Using Plate Reader - 2037-04_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: 44 drypowder compounds at dose in Antifungal Secondary - fibroblasts measuring activity set 5
488836Reversing Antifungal Drug Resistance Measured in Microorganism System Using Plate Reader - 2037-01_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: 44 drypowder compounds at dose in Antifungal Primary measuring activity set 5
488893Antifungal Drug Resistance - Single Agent Toxicity Measured in Microorganism System Using Plate Reader - 2037-07_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference: 34 drypowder compounds at dose in AF Secondary - No Fluconazole measuring activity set 2
488905Antifungal Drug Resistance - Resistant Strain Measured in Microorganism System Using Plate Reader - 2037-02_Inhibitor_Dose_DryPowder_Activity_Set3Confirmatorydepositor-specified cross reference: 28 drypowder compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 3
488907Reversing Antifungal Drug Resistance Measured in Microorganism System Using Plate Reader - 2037-01_Inhibitor_Dose_DryPowder_Activity_Set3Confirmatorydepositor-specified cross reference: 28 drypowder compounds at dose in Antifungal Primary measuring activity set 3
488909Antifungal Drug Resistance - Resistant Strain Measured in Microorganism System Using Plate Reader - 2037-02_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference: 34 drypowder compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 2
488911Antifungal Drug Resistance - Mammalian Cell Toxicity Measured in Cell-Based System Using Plate Reader - 2037-04_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference: 34 drypowder compounds at dose in Antifungal Secondary - fibroblasts measuring activity set 2
488930Reversing Antifungal Drug Resistance Measured in Microorganism System Using Plate Reader - 2037-01_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference: 34 drypowder compounds at dose in Antifungal Primary measuring activity set 2
488932Antifungal Drug Resistance - Single Agent Toxicity Measured in Microorganism System Using Plate Reader - 2037-07_Inhibitor_Dose_DryPowder_Activity_Set4Confirmatorydepositor-specified cross reference: Antifungal Drug Resistance - Single Agent Toxicity set 4
488933Antifungal Drug Resistance - Mammalian Cell Toxicity Measured in Cell-Based System Using Plate Reader - 2037-04_Inhibitor_Dose_DryPowder_Activity_Set3Confirmatorydepositor-specified cross reference: 28 drypowder compounds at dose in Antifungal Secondary - fibroblasts measuring activity set 3
488937Antifungal Drug Resistance - Single Agent Toxicity Measured in Microorganism System Using Plate Reader - 2037-07_Inhibitor_Dose_DryPowder_Activity_Set3Confirmatorydepositor-specified cross reference: 28 drypowder compounds at dose in AF Secondary - No Fluconazole measuring activity set 3
488943Reversing Antifungal Drug Resistance Measured in Microorganism System Using Plate Reader - 2037-01_Inhibitor_Dose_DryPowder_Activity_Set4Confirmatorydepositor-specified cross reference: 54 drypowder compounds at dose in Antifungal Primary measuring activity set 4
488950Antifungal Drug Resistance - Resistant Strain Measured in Microorganism System Using Plate Reader - 2037-02_Inhibitor_Dose_DryPowder_Activity_Set4Confirmatorydepositor-specified cross reference: 54 drypowder compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 4
493064Antifungal Drug Resistance - Resistant Strain Measured in Microorganism System Using Plate Reader - 2037-02_Inhibitor_Dose_DryPowder_Activity_Set5Confirmatorydepositor-specified cross reference: 64 drypowder compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 5
493069Antifungal Drug Resistance - Resistant Strain Measured in Microorganism System Using Plate Reader - 2037-02_Inhibitor_Dose_DryPowder_Activity_Set6Confirmatorydepositor-specified cross reference: 27 drypowder compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 6
493070Antifungal Drug Resistance - Single Agent Toxicity Measured in Microorganism System Using Plate Reader - 2037-07_Inhibitor_Dose_DryPowder_Activity_Set5Confirmatorydepositor-specified cross reference: 27 drypowder compounds at dose in AF Secondary - No Fluconazole measuring activity set 5
493080Antifungal Retest at Dose Measured in Microorganism System Using Plate Reader - 2037-09_Inhibitor_Dose_DryPowder_Activity_Set3Confirmatorydepositor-specified cross reference: 128 drypowder compounds at dose in Retest at Dose measuring activity set 3
493081Antifungal Retest at Dose Measured in Microorganism System Using Plate Reader - 2037-09_Inhibitor_DoseNoFile_DryPowder_ActivityConfirmatorydepositor-specified cross reference: 29 drypowder compounds at dose in Retest at Dose measuring activity set 4
493082Antifungal Drug Resistance - Resistant Strain Measured in Microorganism System Using Plate Reader - 2037-02_Inhibitor_DoseNoFile_DryPowder_ActivityConfirmatorydepositor-specified cross reference: 29 drypowder compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 7
493089Antifungal Retest at Dose Measured in Microorganism System Using Plate Reader - 2037-09_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference: 54 drypowder compounds at dose in Retest at Dose measuring activity set 2
493099Antifungal Drug Resistance - Mammalian Cell Toxicity Measured in Cell-Based System Using Plate Reader - 2037-04_Inhibitor_Dose_DryPowder_Activity_Set4Confirmatorydepositor-specified cross reference: 64 drypowder compounds at dose in Antifungal Secondary - fibroblasts measuring activity set 4
493134Antifungal Drug Resistance - Single Agent Toxicity Measured in Microorganism System Using Plate Reader - 2037-07_Inhibitor_Dose_DryPowder_Activity_Set7Confirmatorydepositor-specified cross reference: 33 drypowder compounds at dose in AF Secondary - No Fluconazole measuring activity set 7
493147Antifungal Drug Resistance - Mammalian Cell Toxicity Measured in Cell-Based System Using Plate Reader - 2037-04_Inhibitor_Dose_DryPowder_Activity_Set6Confirmatorydepositor-specified cross reference: 108 drypowder compounds at dose in Antifungal Secondary - fibroblasts measuring activity set 6
493149Antifungal Drug Resistance - Resistant Strain Measured in Microorganism System Using Plate Reader - 2037-02_Inhibitor_Dose_DryPowder_Activity_Set9Confirmatorydepositor-specified cross reference: 33 drypowder compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 9
493150Antifungal Retest at Dose Measured in Microorganism System Using Plate Reader - 2037-09_Inhibitor_Dose_DryPowder_Activity_Set5Confirmatorydepositor-specified cross reference: 33 drypowder compounds at dose in Retest at Dose measuring activity set 5
493157Antifungal Drug Resistance - Single Agent Toxicity Measured in Microorganism System Using Plate Reader - 2037-07_Inhibitor_Dose_DryPowder_Activity_Set8Confirmatorydepositor-specified cross reference: 29 drypowder compounds at dose in AF Secondary - No Fluconazole measuring activity set 8
504390Antifungal Drug Resistance - Hsp90 Inhibitors Measured in Microorganism System Using Plate Reader - 2037-05_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference: 18 drypowder compounds at dose in AF Secondary - Hsp90 Yeast Reporter measuring activity set 2
504499Antifungal Drug Resistance - Single Agent Toxicity Measured in Microorganism System Using Plate Reader - 2037-07_Inhibitor_Dose_DryPowder_Activity_Set9Confirmatorydepositor-specified cross reference: 28 drypowder compounds at dose in AF Secondary - No Fluconazole measuring activity set 9
504502Antifungal Retest at Dose Measured in Microorganism System Using Plate Reader - 2037-09_Inhibitor_Dose_DryPowder_Activity_Set6Confirmatorydepositor-specified cross reference: 28 drypowder compounds at dose in Retest at Dose measuring activity set 6
504504Antifungal Drug Resistance - Resistant Strain Measured in Microorganism System Using Plate Reader - 2037-02_Inhibitor_Dose_DryPowder_Activity_Set10Confirmatorydepositor-specified cross reference: 28 drypowder compounds at dose in Antifungal Secondary - CaCi8 measuring activity set 10
504525Antifungal Drug Resistance - Mammalian Cell Toxicity Measured in Cell-Based System Using Plate Reader - 2037-04_Inhibitor_Dose_DryPowder_Activity_Set7Confirmatorydepositor-specified cross reference: 28 drypowder compounds at dose in Antifungal Secondary - fibroblasts measuring activity set 7
Description:
Primary Collaborators:
Susan Lindquist, Whitehead Institute, sll@wi.mit.edu
Luke Whitesell, Whitehead Institute, whitesell@wi.mit.edu

Biological Relevance:
Acquired drug resistance by medically relevant microorganisms poses a grave threat to human health and has enormous economic consequences. Fungal pathogens pose a particular challenge because they are eukaryotes and share many of the same mechanisms that support the growth and survival of the cells comprising their human hosts. The number of drug classes that have distinct targets in fungi is very limited and the usefulness of current antifungal drugs is compromised owing to either dose-limiting host toxicity or the frequent emergence of high grade resistance. The objective of this project is to discover compounds capable of reversing fungal drug resistance, thereby making currently available antifungals safer and more effective. In previously published work, we have established that inhibition of the molecular chaperon Hsp90 can abrogate drug resistance in diverse fungi including species of both Candida and Aspergillus. Candida albicans is a major fungal pathogen of humans and causes life-threatening systemic disease, particularly in immunocompromised hosts. At concentrations that demonstrate no antifungal activity on their own, classical Hsp90 inhibitors dramatically reduce azole antibiotic resistance of clinical isolates and transform conventional fungistatic azole compounds into a fungicidal drug combination. Hsp90 inhibitors can also revert the echinocandin resistance of clinical isolates of Aspergillus fumigatus, the causal agent of lethal pulmonary disease.

To gain a better understanding of the mechanisms by which Hsp90 inhibition reverts antifungal drug resistance, we have completed extensive studies in the genetically tractable fungus S. cerevisiae. This work makes clear that the resistance phenotype mediated by a wide variety of specific mutations is contingent on intact Hsp90-dependent fungal stress responses. Such responses allow the organism to tolerate the stresses imposed by drug exposure itself and/or accommodate to the mutations that mediate resistance to the drug. For example, genetic compromise of the key fungal stress signaling molecule calcineurin, itself an Hsp90 client protein, faithfully phenocopies the effects of Hsp90 inhibition. Consistent with these genetic data, known calcineurin inhibitors such as cyclosporine A (CsA) also revert drug resistance in S. cerevisiae as well as clinical isolates of fluconazole-resistant C. albicans.

Our findings suggest that Hsp90 inhibitors could greatly improve the ability to control otherwise lethal fungal infections in severely immunocompromised hosts, especially cancer patients undergoing high dose chemotherapy and/or bone marrow transplant procedures. Although the Hsp90 inhibitors under development appear to be well-tolerated in early phase cancer clinical trials, compromise of host Hsp90 function could have very deleterious effects in the context of active infection and the associated stresses of fever and cardiovascular instability. Likewise, profound compromise of host immune responses with inhibitors of calcineurin such cyclosporine A and FK506 seems unwise in efforts to control invasive fungal infection. To address these concerns and realize the exciting therapeutic potential of our basic biological insights, this HTS project seeks to identify new fungal-selective inhibitors of these specific targets and/or other components of fungal stress response pathways that enable the emergence and maintenance of resistance to current antifungal drugs.

Project Goal:
INHIBITORS- primary screen in the presence of fluconazole

Keywords:
Candida albicans, drug resistance, fluconazole, Hsp90, Calcineurin, stress response

History / Results Summary (for all Assays related to this goal):

FOR EACH ASSAY::
HTS - AID# 1979
Assay Biology/Type: Organism
Readout Technology: Plate Reader
Target Pathway: N/A
Test concentration(s): 9.5 uM (1536 plates), 25 uM (384 plates)
Activity criterion: >75% inhibition
# Substances evaluated: 302509
# Substances active: 1737
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML_NUMML number assigned to the compound.String
Additional Information
Grant Number: 1 R03 MH086456-01

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
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