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PhD by Research PRogramme (Infection and Immunity)

Employer
Global Academy Jobs
Location
Singapore
Closing date
Jan 31, 2017

Job Details

Research Project Title: Suffocating Tuberculosis: Oxidative Phosphorylation as a Target Space for Next-generation Antitubercular Drugs

Principal Investigator: Associate Professor Kevin Pethe, LKCMedicine

Co-supervisor: Associate Professor Eric Yap, LKCMedicine

Project Description:

Background:  

While being phenotypic drug resistant to most standard antituberculosis drugs, hypoxic non-replicating mycobacteria are exquisitely sensitive to agents that perturb the maintenance of the proton motive force. Hence, small-molecules targeting specific components of the respiratory chain are expected to be effective at sterilizing hypoxic non-replicating mycobacteria and at shortening the treatment time of tuberculosis. This is supported by the clinical development of bedaquiline, a newly approved anti-tuberculosis drug that inhibits the mycobacterial F0F1 ATP synthase. 

We recently reported on Q203, a clinical-stage drug candidate for the treatment of tuberculosis. Q203 represents a first-in-class drug that kill Mycobacterium tuberculosis by inhibiting the bc1-aa3 branch of the respiratory network. Genetic evidences suggest that Q203 interferes with the binding of menaquinol to the qcrB subunit of the cytochrome bc1, thereby blocking electron flow to the terminal oxidase and ATP synthesis.

The aim of the proposal is to validate further the cytochrome bc-1 (and other respiratory complexes) as drug targets for the development of next-generation antitubercular drugs.  
 
Proposed work:

1. Investigate mode of action of Q203 and characterize the molecular interaction with the qcrB sub-unit of the cytochrome bc-1.

2. Development of innovative drug screening to identify small-molecules that act in synergy with Q203.

3. Identification of synthetic lethal genetic interactions with the bc1-aa3 respiratory branch to validate conditionally-essential drug targets.

If you have questions regarding this project, please email the Principal Investigator, Associate Professor Kevin Pethe, at kevin.pethe@ntu.edu.sg

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