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DEVELOPMENT OF A FLUORESCENT DRUG SCREENING PLATFORM FOR INHIBITORS OF MYCOBACTERIUM TUBERCULOSIS PROTEIN-PROTEIN INTERACTIONS

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Date Issued:
2015
Abstract/Description:
Tuberculosis (TB) is a respiratory disease caused by Mycobacterium tuberculosis (Mtb) that kills around 1.3 million people annually. Multi-drug resistant TB (MDR-TB) strains are increasingly encountered, in part resulting from shortcomings of current TB drug regimens that last between six to nine months. Patients may stop taking the antibiotics during their allotted regimen, leading to drug resistant TB strains. Novel drug screening platforms are therefore necessary to find drugs effective against MDR-TB. In order to discover compounds that target under-exploited pathways that may be essential only in vivo, the proposed screening platform will use a novel approach to drug discovery by blocking essential protein-protein interactions (PPI). In Mtb, PPI can be monitored by mycobacterial protein fragment complementation (M-PFC). This project will re-engineer the M-PFC assay to include the red fluorescent mCherry reporter for increased efficiency and sensitivity in high-throughput screening applications. To optimize the mCherry assay, we have developed fluorescent M-PFC reporter strains to monitor distinct PPI required for Mtb virulence: homodimerization of the dormancy regulator DosR. A drug screen will then identify novel compounds that inhibit this essential PPI. The screen will involve positional-scanning combinatorial synthetic libraries, which are made up of chemical compounds with varying side chains. This work will develop novel tools for TB drug discovery that could identify new treatments for the emerging world threat of MDR-TB.
Title: DEVELOPMENT OF A FLUORESCENT DRUG SCREENING PLATFORM FOR INHIBITORS OF MYCOBACTERIUM TUBERCULOSIS PROTEIN-PROTEIN INTERACTIONS.
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Name(s): Versfeld, Zina, Author
Rohde, Kyle, Committee Chair
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2015
Publisher: University of Central Florida
Language(s): English
Abstract/Description: Tuberculosis (TB) is a respiratory disease caused by Mycobacterium tuberculosis (Mtb) that kills around 1.3 million people annually. Multi-drug resistant TB (MDR-TB) strains are increasingly encountered, in part resulting from shortcomings of current TB drug regimens that last between six to nine months. Patients may stop taking the antibiotics during their allotted regimen, leading to drug resistant TB strains. Novel drug screening platforms are therefore necessary to find drugs effective against MDR-TB. In order to discover compounds that target under-exploited pathways that may be essential only in vivo, the proposed screening platform will use a novel approach to drug discovery by blocking essential protein-protein interactions (PPI). In Mtb, PPI can be monitored by mycobacterial protein fragment complementation (M-PFC). This project will re-engineer the M-PFC assay to include the red fluorescent mCherry reporter for increased efficiency and sensitivity in high-throughput screening applications. To optimize the mCherry assay, we have developed fluorescent M-PFC reporter strains to monitor distinct PPI required for Mtb virulence: homodimerization of the dormancy regulator DosR. A drug screen will then identify novel compounds that inhibit this essential PPI. The screen will involve positional-scanning combinatorial synthetic libraries, which are made up of chemical compounds with varying side chains. This work will develop novel tools for TB drug discovery that could identify new treatments for the emerging world threat of MDR-TB.
Identifier: CFH0004785 (IID), ucf:45369 (fedora)
Note(s): 2015-05-01
B.S.
Medicine, Dept. of Molecular Biology and Microbiology
Bachelors
This record was generated from author submitted information.
Subject(s): TB
tuberculosis
drug screening
protein-protein interactions
fluorescence
M-PFC
Mycobacterium tuberculosis
multi-drug resistance
antibiotic resistance
drug discovery
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFH0004785
Restrictions on Access: campus 2020-04-01
Host Institution: UCF

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