This proposal's aim is to develop a technology platform based upon a common characteristic of both Gram-positive and Gram-negative pathogens: an absolute requirement for iron. The PI has focused on iron-activated repressors, which control the expression of iron uptake and storage genes in addition to many virulence genes, as targets for a new class of antibiotics. This approach's validity has been demonstrated using the diphtheria toxin repressor, DtxR. Iron independent hyper-repressor mutants of DtxR have been isolated utilizing a recently published genetic screen. These mutants were used to generate partial diploids in Mycobacterium tuberculosis that resulted in the attenuation of virulence in mouse challenge experiments. The PI proposes to expand this approach and target IdeR in M. tuberculosis and IdeRa in M. avium. The effects of iron independent mutations in these genes will be assessed in growth assays of M. tuberculosis and M. avium. If these mutants display altered viability then the IdeR/IdeRa genes will be used to modify and develop the PSTD system as a specific screen for anti-mycobacterial compounds. PROPOSED COMMERCIAL APPLICATION: Application of existing primary assay as a tool for identification of lead anti-microbial compoundsfor the treatment of antibiotic resistant bacterial infections. Potential to develop antibiotics of last resort for infection by a number of microbial pathogens including application as a primary therapy or in combinatorial therapy to enhance enhance efficacy of existing antibiotics. Potential to achieve large percentage of annual $US6 billion antimicrobial drug market
