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BioAssay: AID 434999

Summary of Assays used to Identify Novel Compounds That Sensitize Mycobacterium Tuberculosis to Beta-lactam Antibiotics

With approximately two billion people who have been exposed to Mycobacterium tuberculosis (M.tb) world-wide, tuberculosis has been declared a global health emergency by the WHO. In 2008, there were 9.4 million new cases of tuberculosis and approximately 2 million deaths associated with the disease, representing a nearly 10% increase in incidence since 2006. Of particular concern is the more ..
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 Related BioAssays
 Related BioAssays
AID: 434999
Data Source: Southern Research Specialized Biocontainment Screening Center (TB_SL_Summ)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2010-06-16
Modify Date: 2011-05-09
Related Experiments
AIDNameTypeComment
434955Screen to Identify Novel Compounds That Sensitize Mycobacterium Tuberculosis to Beta-lactam AntibioticsConfirmatorydepositor-specified cross reference: Screen to Identify Novel Compounds That Sensitize Mycobacterium Tuberculosis to Beta-lactam Antibiot
434958A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Sensitize Mycobacterium Tuberculosis to Beta-Lactam AntibioticsConfirmatorydepositor-specified cross reference: A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Sensitize Mycobacterium Tuber
434987Screen and Counter Screen to Identify Novel Compounds that Selectively Sensitize Mycobacterium Tuberculosis to Beta-lactam AntibioticsConfirmatorydepositor-specified cross reference: Screen and Counter Screen to Identify Novel Compounds that Selectively Sensitize Mycobacterium Tuber
485340Secondary Screen to Confirm Synergistic Effect of Compounds with Meropenem Against Mycobacterium TuberculosisConfirmatorydepositor-specified cross reference: Secondary Screen to Confirm Synergistic Effect of Compounds with Meropenem Against Mycobacterium Tub
493013A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Sensitize Mycobacterium Tuberculosis to Beta-Lactam Antibiotics (2)Confirmatorydepositor-specified cross reference: A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Sensitize Mycobacterium Tuber
504702Screen to Identify Novel Compounds That Sensitize Mycobacterium Tuberculosis to Beta-lactam Antibiotics (2)Confirmatorydepositor-specified cross reference: Secondary Screen to Confirm Synergistic Effect of Compounds with Meropenem Against Mycobacterium Tub
504703Screen and Counter Screen to Identify Novel Compounds that Selectively Sensitize Mycobacterium Tuberculosis to Beta-lactam Antibiotics (2)Confirmatorydepositor-specified cross reference: Screen and Counter Screen to Identify Novel Compounds that Selectively Sensitize Mycobacterium Tuber
504713A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Sensitize Mycobacterium Tuberculosis to Beta-Lactam Antibiotics (3)Confirmatorydepositor-specified cross reference: A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Sensitize Mycobacterium Tuber
Description:
Southern Research's Specialized Biocontainment Screening Center (SRSBSC)
Southern Research Institute (Birmingham, Alabama)
NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Assay Provider: Dr. William Bishai, Johns Hopkins University Tuberculosis Research Center
Award: 1 R03 MH084877-01A1

With approximately two billion people who have been exposed to Mycobacterium tuberculosis (M.tb) world-wide, tuberculosis has been declared a global health emergency by the WHO. In 2008, there were 9.4 million new cases of tuberculosis and approximately 2 million deaths associated with the disease, representing a nearly 10% increase in incidence since 2006. Of particular concern is the emergence of multiple drug resistant (MDR) and extremely drug resistant (XDR) strains for which there are few, if any effective treatments. In 2008, MDR and XDR-TB accounted for 0.5 million deaths globally. The emergence of these resistant strains is underscoring the need for new drugs that can combat M.tb. The beta-lactam and macrolide classes of antibiotics are largely useless against M.tb because of limited bacterial penetration and degradation of the drugs by beta-lactamases, which are constitutively expressed by the mycobacterium. The identification of compounds that would sensitize M.tb to this large class of known antibiotics is an attractive route of discovery.

Primary and Confirmatory screens were developed to screen large compound libraries in a synthetic lethality, 384-well format high throughput screen in BSL-3 containment at Southern Research Institute. This assay was screened with a set of plates being run in the presence of a sub-lethal (~IC10) dose of the representative beta-lactam antibiotic, meropenem.

Data from both the primary and confirmatory screens was compared to like data run in the absence of meropenem. Compounds were chosen as active based on differential inhibition between the two replicates with the higher inhibition values being in the meropenem plates.


Primary AID: 434955
Title: Primary Screen to Identify Novel Compounds that Sensitize Mycobacterium Tuberculosis to Beta-lactam Antibiotics
Number of compounds: 328,013
Activity Criteria: % Inhibition with meropenem >=74.03% and % Inhibition with no meropenem >40% less that result with meropenem.
Number of Active compounds: 1,343


Confirmatory AID: 434955
Title: Confirmatory Screen to Identify Novel Compounds that Sensitize Mycobacterium Tuberculosis to Beta-lactam Antibiotics
Number of compounds: 1,202
Activity Criteria: % Inhibition at any dose in the presence of meropenem >= 30% Number of Active compounds: 876

Confirmatory AID: 504702
Title: Confirmatory Screen to Identify Novel Compounds that Sensitize Mycobacterium Tuberculosis to Beta-lactam Antibiotics
Number of compounds: 157
Activity Criteria: % Inhibition at any dose in the presence of meropenem >= 30% Number of Active compounds: 67

Counterscreen for selectivity AID: 434987
Title: Screen and Counter Screen to Identify Novel Compounds that Selectively Sensitize Mycobacterium Tuberculosis to Beta-lactam Antibiotics.
Number of compounds: 1,202
Activity Criteria: % Inhibition at any dose in the presence of meropenem >= 30% and SI (IC50 with no meropenem/IC50 in presence of meropenem) >=2.5.
Number of Active compounds: 372

Counterscreen for selectivity AID: 504703
Title: Screen and Counter Screen to Identify Novel Compounds that Selectively Sensitize Mycobacterium Tuberculosis to Beta-lactam Antibiotics.
Number of compounds: 157
Activity Criteria: % Inhibition at any dose in the presence of meropenem >= 30% and SI (IC50 with no meropenem/IC50 in presence of meropenem) >=2.5.
Number of Active compounds: 30

Cytotoxicity Screen using Vero Cells
AID: 434958
Title: A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Sensitize Mycobacterium Tuberculosis to Beta-Lactam Antibiotics
Number of compounds: 1,202
Activity Criteria: % Viability < 70%
Number of Active compounds: 397

AID: 493013
Title: A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Sensitize Mycobacterium Tuberculosis to Beta-Lactam Antibiotics (2)
Number of compounds: 111
Activity Criteria: % Viability < 70%
Number of Active compounds: 52

AID: 504713
Title: A Cell Based Secondary Assay To Explore Cytotoxicity of Compounds that Sensitize Mycobacterium Tuberculosis to Beta-Lactam Antibiotics (2)
Number of compounds: 131
Activity Criteria: % Viability < 70%
Number of Active compounds: 40

Dose Response Matrix containing serial dilutions meropenem combined with serial dilutions of selected active test compounds
AID: 483540
Title: Secondary Screen to Confirm Synergistic Effect of Compounds with Meropenem Against Mycobacterium Tuberculosis
Number of compounds: 99
Activity Criteria: >4 fold increase in efficacy where fold increase in efficacy = IC50 of meropenem alone (3.96 uM)/IC50 of meropenem combined with the IC50 concentration of test compound as determined in confirmatory assay AID 434955.
Number of Active compounds: 3
Additional Information
Grant Number: R03 MH084877-01A1

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