Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/144391
Title: IDENTIFICATION OF BORTEZOMIB AS MYCOBACTERIAL CASEINOLYTIC PROTEASE INHIBITOR
Authors: GRACE NGAN JIE YIN
Keywords: Bortezomib, Mycobacterium, Caseinolytic Protease, Inhibitor
Issue Date: 4-Jan-2017
Citation: GRACE NGAN JIE YIN (2017-01-04). IDENTIFICATION OF BORTEZOMIB AS MYCOBACTERIAL CASEINOLYTIC PROTEASE INHIBITOR. ScholarBank@NUS Repository.
Abstract: Tuberculosis (TB) diseases remain endemic worldwide. This situation is compounded by the rising of multidrug-resistant TB that calls for an urgent medical need for new drugs with new mechanism of action to control TB diseases. Here, we developed a novel type of antibacterial screen, a target mechanism-based whole-cell screen that used mycobacterial caseinolytic protease proteolytic subunits ClpP1P2 as a target to screen for the inhibitor. A high throughput screen identified Bortezomib, a human proteasome drug, as a potent inhibitor of ClpP1P2-activity and bacterial growth. A plethora of secondary assays demonstrated that Bortezomib indeed exerts its antimicrobial activity via inhibition of ClpP1P2. Characterization of Bortezomib led us to discover that tubercle bacilli and fast-growing mycobacterium evolve different mechanisms of resistance to Bortezomib. This work demonstrates the feasibility of target mechanism-based whole-cell screens, provides chemical validation of ClpP1P2 as a mycobacterial target and identifies Bortezomib as a new lead compound for tuberculosis.
URI: http://scholarbank.nus.edu.sg/handle/10635/144391
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