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Old Structures - New Targets for Antivirulence Salicylidene Acylhydrazide Compounds
Select Biosciences Ltd

Salicylidene acylhydrazide compounds have been demonstrated to perturb the function of the type three secretion of many important human pathogens including Escherichia coli O157 and Yersinia pseudotuberculosis. The actual protein targets of these compounds had, to this date, been unknown. In this work we present the identification and verification of three such protein targets. Each protein was identified using a combination of affinity chromatography and Far-western analyses followed by phenotypic testing of defined bacterial mutants using in vitro and in vivo assays. , , The structure of the target protein with the greatest effect on virulence in Yersinia pseudotuberculosis was solved in 3 forms by X-ray crystallography. In combination with studies of inactive mutants, and conformational changes in the protein caused by redox active state, we present localised regions likely to bind to the drug. Work is under way to solve the structure of protein and compound that will permit refinement of the salicylidene acylhydrazides with the long-term goal of developing clinically-useable drugs.

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