Objective 4: Target Discovery
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To identify targets and inhibitors of key enzymatic and metabolic pathways predicted from the Wolbachia genome.
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To use bioinformatics to identify the ‘essential gene set’ of Wolbachia and multi-step computational approaches to identify potential drug targets and develop a surrogate screening system.
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To use aptamer technology to identify inhibitors of novel drug targets to incorporate into HTS.
What are the genes essential to Wolbachia survival?
What processes does the bacteria contribute to the symbiosis?
A genomic filtering approach to discovering potential drug targets will be applied to Wolbachia (see Figure). The Wolbachia genome is predicted to encode approximately 800 genes of which probably 60% do not share significant similarity with mammals. To identify the potentially essential genes in Wolbachia, we plan to generate an ‘essential bacterial gene set’ by mining data sources. Using this multi-step computational approach, we will identify a pool of gene products in Wolbachia that encode potential endosymbiont drug targets that likely do not exist in mammals. This process would be repeated on a regular basis to capture the ever-expanding sequence information and gene function data.
The output of this in silico screening will then be fed into appropriate high throughput drug screens. This will involve either production of recombinant proteins for the aptamer-based inhibitor screening and/or generation of appropriate complemented mutant E. coli strains.
