Systems-based screen of compounds that target nitrogen metabolism of Mycobacterium tuberculosis.

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New drugs active against Mycobacterium tuberculosis (Mtb) are urgently needed but conventional screens have developed only a handful in the last fifty years. Metabolism is central to cell replication and a source of many enzymes that might be targeted with novel drugs. A lot of interest has recently focussed on carbon metabolism but nitrogen is also an essential nutrient of Mtb that is likely to provide many novel drug targets. In our previous BBSRC-supported systems-based study of nitrogen metabolism of Mtb, we identified the major amino acids captured from host cells that are used as sources of nitrogen in Mtb and showed that the SerC transaminase is essential for intracellular replication. In this study will first measure the virulence of we will first measure the virulence of a SerC mutant of Mtb in the BALB/c mouse model of infection. The next step will be to screen a chemical compound library to identify any that target SerC. To identify compounds that specifically target SerC, we will search for those that are active against wild-type Mtb but not an auxotrophic SerC mutant strain supplemented with serine. We will then extend the study to other key genes involved in nitrogen metabolism and also genes involved in uptake of amino acids from host cells and screen auxotrophic mutants of these gene against the compound library. Finally, we will develop a computer model of nitrogen and carbon metabolism in Mtb that can be used to design synergistic combinations of drugs that target nitrogen metabolism and test predictions of the model experimentally.