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Drug mechanism and protein function in live mycobacteria


Small molecule-based chemotherapy is the most important intervention for tuberculosis (TB) and there is an urgent and generally acknowledged need for new anti-tuberculosis drugs.

It is notoriously difficult to identify and characterise drug targets in Myco bacterium tuberculosis Mtb as we do not yet possess direct means to investigate protein function or protein-protein and protein-ligand interactions within mycobacteria. Since drug sensitivity in Mtb often results from complex interaction of multiple proteins and other biomolecules, it is essential to study protein and drug mechanisms in their natural environment.

This proposal describes novel strategies to study protein and drug function, which will be developed in the model relative of Mtb, Mycobacterium smegmatis, and subsequently within Mtb itself. These strategies are based on innovative technologies developed in the host laboratory:

The first is a split-protein sensor derived from the enzyme N-(5-phosphoribosyl)-anthranilate isomerase Trp1p from Saccharomycescerevisiae, which allows the detection of protein-protein interactions in the membrane or the cytoplasm, and the second is a method for labelling fusion-proteins with synthetic probes in vivo. Used together these techniques should allow the detection of protein-ligand interactions, and hence the identification of the targets and mechanisms of candidate drugs.

The tools developed within this project should provide the research community with innovative tools to study protein function in mycobacteria, t hereby significantly increasing the success rate for the development of new small molecule-based drugs against tuberculosis.

Call for proposal

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