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BioAssay: AID 687034

Broad Institute Elucidation of the physiology of non-replicating, drug tolerant Mycobacterium tuberculosis: Probe to inhibit the Transition from Non-Replication to Replication 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
 Related BioAssays
AID: 687034
Data Source: Broad Institute (7107_Inhibitor_Project)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2013-06-19
Modify Date: 2013-09-20
Related Experiments
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AIDNameTypeProbeComment
488890Elucidation of physiology of non-replicating, drug-tolerant Mycobacterium tuberculosisConfirmatory depositor-specified cross reference: Primary screen and Confirmatory dose response of hits
488929Elucidation of physiology of non-replicating, drug-tolerant Mycobacterium tuberculosis - SummarySummary1 depositor-specified cross reference
489018A Cell Based Secondary Assay to Explore Cytotoxicity in HepG2 Cells of Compounds that Modulate Non-Replicating, Drug-tolerant Mycobacterium tuberculosisConfirmatory depositor-specified cross reference: Hits from Primary screen in cytotoxicity dose response with HepG2 cells.
489025A Cell Based Secondary Assay to Explore Cytotoxicity in THP-1 Cells of Compounds that Modulate Non-Replicating, Drug-tolerant Mycobacterium tuberculosisConfirmatory depositor-specified cross reference: Hits from Primary screen in cytotoxicity dose response with THP1 cells.
492952A Cell Based Secondary Assay to Explore Compounds that Modulate Non-Replicating, Drug-tolerant Compounds in Replicating H37Rv TB of Mycobacterium tuberculosisConfirmatory depositor-specified cross reference: A Cell Based Secondary Assay to Explore Compounds that Modulate Non-Replicating, Drug-tolerant Compo
492998A Cell Based Secondary Assay to Explore Cytotoxicity in Vero E6 Cells of Compounds that Modulate Non-Replicating, Drug-tolerant Mycobacterium tuberculosisConfirmatory depositor-specified cross reference: Hits from Primary screen in cytotoxicity dose response with Vero E6 cells.
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 depositor-specified cross reference
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 depositor-specified cross reference: Counterscreen for inhibitors of non replicating M. tb using log phase replicating mycobacteria
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 depositor-specified cross reference
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 depositor-specified cross reference
651851Counterscreen for inhibitors of non replicating M. tb using log phase replicating mycobacteriaConfirmatory depositor-specified cross reference
651856Secondary assay to identify inhibitors of non-replicating M. tb using luciferase expression without log phase outgrowthConfirmatory depositor-specified cross reference
651946HeLa Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader - 7071-04_Other_Dose_DryPowder_ActivityConfirmatory depositor-specified cross reference
651947HepG2 Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader - 7071-02_Other_Dose_DryPowder_ActivityConfirmatory depositor-specified cross reference
651949HEK293 Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader - 7071-01_Other_Dose_DryPowder_Activity_Set6Confirmatory depositor-specified cross reference
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
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
687033Broad Institute Elucidation of the physiology of non-replicating, drug tolerant Mycobacterium tuberculosis: Probe for both Non-Replicating & Replicating organisms 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 sub optimal 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.


Project Goal:
The available drugs for TB predominately operate via the inhibition of the bacterial metabolism and therefore are only able to target replicating bacteria. Consequently, TB bacilli existing in metabolically dormant, non-replicating states in vivo demonstrate significant drug tolerance. Hence identification of small molecule probes that selectively inhibit the transition of Mycobacterium tuberculosis from a non replicating to a replicating state will play a powerful role in understanding the physiology of the non-replicating states and/or the mechanism of switching from non-replicating to replicating state.


Target Activity: MIC 90 < 5 uM in primary assay.
Selectivity:
1. IC90 in Log replication assay > 40 uM and at least 10X IC90 in primary assay and
2. IC90 in Luc starvation assay > 40 uM and at least 10X IC90 in primary assay
Biological Mode of Action: Cellular
Cellular Toxicity: Non-toxic to mammalian cells at 3X effective IC50
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
Additional Information
Grant Number: 1 R03 MH087444-01

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