The long term goal of the research proposed here is the development of new antibiotics effective against Mycobacterium tuberculosis, the leading infectious cause of death in the world today. Novel drug targets are proposed - seven enzymes that together comprise the shikimate metabolic pathway in Mycobacterium tuberculosis. In plants and microbes, the shikimate pathway synthesizes the aromatic amino acids and other aromatic compounds that are essential for survival. No equivalent metabolic pathway exists in humans or other mammals. This makes the shikimate pathway a very attractive drug target, as inhibitors of the pathway may have low toxicity in humans. The research proposed here exploits the treasure-trove of information in the recently complete genome sequence of a virulent strain of Mycobacterium tuberculosis. The gene sequence will be used to clone, express, and purify shikimate enzymes from the pathogen. Functional enzyme assays suitable for high throughput screening for inhibitors will be developed. Compounds that are known -to inhibit the shikimate pathway in other organisms will also be tested against the mycobacterial enzymes for their ability to block enzyme function. Compounds found to inhibit the pathway in this molecular level screen will serve as lead compounds in the complete drug screening program to be developed in Phase II.
The immediate goal of the Phase I research is to develop high throughput drug screening assays for inhibitors of two enzymes that are vital for M.tb, but absent from mammals. The long term goal is to identify lead candidates for antituberculosis drugs that may have low toxicity. A Patent search has revealed no precedents that would preclude a proprietary position for Sequella and the University of South Alabama.
