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BioAssay: AID 687033

Broad Institute Elucidation of the physiology of non-replicating, drug tolerant Mycobacterium tuberculosis: Probe for both Non-Replicating & Replicating organisms Inhibitor Probe Project

Over one third of the world's population is infected with tuberculosis. In 1993, the World Health Organization declared a global health emergency with the resurgence of tuberculosis in the setting of HIV infection and with the emergence of multi-drug resistant TB. In 2004, 14.6 million people had active TB, 8.9 million new cases were documented, and 1.7 million deaths were attributed to TB. more ..
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 Related BioAssays
AID: 687033
Data Source: Broad Institute (7108_Inhibitor_Project)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2013-06-19
Related Experiments
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AIDNameTypeProbeComment
488929Elucidation of physiology of non-replicating, drug-tolerant Mycobacterium tuberculosis - SummarySummary1 depositor-specified cross reference
743162TB: CFU Replicating Measured in Microorganism System Using Imaging - 7108-01_Inhibitor_Dose_DryPowder_ActivityOther depositor-specified cross reference
743163TB: CFU Starved Measured in Microorganism System Using Imaging - 7108-02_Inhibitor_Dose_DryPowder_ActivityOther depositor-specified cross reference
743164TB:CFU starved Measured in Microorganism System Using Imaging - 7108-04_Inhibitor_Dose_DryPowder_ActivityConfirmatory depositor-specified cross reference
743165TB: CFU replicating Measured in Microorganism System Using Imaging - 7108-03_Inhibitor_Dose_DryPowder_ActivityConfirmatory depositor-specified cross reference
743174TB: Log Assay, OD 600 Measured in Microorganism System Using Plate Reader - 7108-05_Inhibitor_Dose_DryPowder_ActivityConfirmatory depositor-specified cross reference
743175Elucidation of physiology of non-replicating, drug-tolerant Mycobacterium tuberculosis Measured in Microorganism System Using Plate Reader - 2157-01_Inhibitor_Dose_DryPowder_ActivityConfirmatory depositor-specified cross reference
743183Secondary assay to identify inhibitors of non-replicating M. tb using luciferase expression without log phase outgrowth Measured in Microorganism System Using Plate Reader - 2157-04_Inhibitor_Dose_DryPowder_Activity_Set4Confirmatory depositor-specified cross reference
743186TB:Log Assay, OD600 Measured in Microorganism System Using Plate Reader - 2157-02_Inhibitor_Dose_DryPowder_Activity_Set4Confirmatory depositor-specified cross reference
743404TB: CFU replicating Measured in Microorganism System Using Imaging - 7108-05_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatory depositor-specified cross reference
743450TB:CFU starved Measured in Microorganism System Using Imaging - 7108-06_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatory depositor-specified cross reference
743485 On Hold
743486 On Hold
1035471 On Hold
1035472 On Hold
1035473 On Hold
488890Elucidation of physiology of non-replicating, drug-tolerant Mycobacterium tuberculosisConfirmatory same project related to Summary assay
489018A Cell Based Secondary Assay to Explore Cytotoxicity in HepG2 Cells of Compounds that Modulate Non-Replicating, Drug-tolerant Mycobacterium tuberculosisConfirmatory same project related to Summary assay
489025A Cell Based Secondary Assay to Explore Cytotoxicity in THP-1 Cells of Compounds that Modulate Non-Replicating, Drug-tolerant Mycobacterium tuberculosisConfirmatory same project related to Summary assay
492952A Cell Based Secondary Assay to Explore Compounds that Modulate Non-Replicating, Drug-tolerant Compounds in Replicating H37Rv TB of Mycobacterium tuberculosisConfirmatory same project related to Summary assay
492998A Cell Based Secondary Assay to Explore Cytotoxicity in Vero E6 Cells of Compounds that Modulate Non-Replicating, Drug-tolerant Mycobacterium tuberculosisConfirmatory same project related to Summary assay
651617Counterscreen for inhibitors of non replicating M. tb using log phase replicating mycobacteria Measured in Microorganism System Using Plate Reader - 2157-02_Inhibitor_Dose_DryPowder_ActivityConfirmatory same project related to Summary assay
651618Counterscreen for inhibitors of non replicating M. tb using log phase replicating mycobacteria Measured in Microorganism System Using Plate Reader - 2157-02_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatory same project related to Summary assay
651619Secondary assay to identify inhibitors of non-replicating M. tb using luciferase expression without log phase outgrowth Measured in Microorganism System Using Plate Reader - 2157-04_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatory same project related to Summary assay
651620Secondary assay to identify inhibitors of non-replicating M. tb using luciferase expression without log phase outgrowth Measured in Microorganism System Using Plate Reader - 2157-04_Inhibitor_Dose_DryPowder_ActivityConfirmatory same project related to Summary assay
651850Inhibition of Mycobacterium tuberculosis during logarithmic growth, as enumerated by colony forming units_2157-05_Inhibitor_Dose_DryPowder_ActivityConfirmatory same project related to Summary assay
651851Counterscreen for inhibitors of non replicating M. tb using log phase replicating mycobacteriaConfirmatory same project related to Summary assay
651856Secondary assay to identify inhibitors of non-replicating M. tb using luciferase expression without log phase outgrowthConfirmatory same project related to Summary assay
651857Inhibition of Mycobacterium tuberculosis during starvation growth, as enumerated by colony forming units_2157-06_Inhibitor_Dose_DryPowder_ActivityConfirmatory same project related to Summary assay
651946HeLa Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader - 7071-04_Other_Dose_DryPowder_ActivityConfirmatory same project related to Summary assay
651947HepG2 Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader - 7071-02_Other_Dose_DryPowder_ActivityConfirmatory same project related to Summary assay
651949HEK293 Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader - 7071-01_Other_Dose_DryPowder_Activity_Set6Confirmatory same project related to Summary assay
687034Broad Institute Elucidation of the physiology of non-replicating, drug tolerant Mycobacterium tuberculosis: Probe to inhibit the Transition from Non-Replication to Replication Inhibitor Probe ProjectSummary same project related to Summary assay
Description:
Biological Relevance:
Over one third of the world's population is infected with tuberculosis. In 1993, the World Health Organization declared a global health emergency with the resurgence of tuberculosis in the setting of HIV infection and with the emergence of multi-drug resistant TB. In 2004, 14.6 million people had active TB, 8.9 million new cases were documented, and 1.7 million deaths were attributed to TB. Future projections are even more alarming, due to the catastrophic synergy between TB and HIV. In this setting however, we have been forced to rely on suboptimal drugs that were developed in the 1950-60's, with TB drug development vanishing after the 1970's. At present, chemotherapy for TB requires at least six months of a complex multi-drug regimen. Treatment length greatly hinders effective TB control due to the challenges of compliance, which contribute to the development of multi-drug resistance. Despite the alarming implications for public health, research funding has lagged far behind the problem, and the pharmaceutical industry has all but ignored TB. New agents that achieve more rapid cures would transform the current pandemic; however, major barriers exist to developing such novel therapeutics including the lack of understanding of the in vivo physiologic states of TB bacilli as they adapt to the host microenvironment in order to survive for extended periods of time.
Goal Summary:
Project Goal:
While anti-tuberculosis drugs can kill the culprit Mycobacterium tuberculosis (TB) bacilli in in vitro, axenic culture in a few days, treatment of an infected human host takes on the order of 6 months. Treating clinically latent forms of TB requires even longer periods of time, ~ 9 months. The difference between the in vitro and in vivo requirement is thought to be due to TB bacilli existing in a different physiologic state in vivo that is potentially "drug tolerant" due to the assumption of a metabolically dormant, non-replicating state. Understanding what functions are essential in these dormant bacilli and the mechanisms by which they switch between non-replicating and replicating states would be invaluable to the development of more effective, potentially shorter course TB therapy. Because of the current limitations in TB genetics resulting in the inadequate ability to study essential gene functions, the identification and use of small molecule probes that modulate survival of non-replicating and replicating TB bacilli, with good selectivity for TB over host cell types will help the elucidation of TB biology and the development of new therapeutics against TB.

Target Activity:
1. IC90 in Luc starvation assay < 10 uM
2. Active against replicating TB at IC90 < 10 uM
Biological Mode of Action: Cellular
Cellular Toxicity: Non-toxic to mammalian cells at 3X effective IC50 or at 30 uM
Functional Groups to be avoided:
1. Chemically reactive groups
2. Metabolically labile groups
3. pH sensitive or hydrolytically unstable
Chemical Solubility Criteria: Soluble in aqueous solution
Categorized Comment - additional comments and annotations
From PubChem:
Assay Format: Organism-based
Additional Information
Grant Number: 1 R03 MH087444-01

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