Tuberculosis is the world's leading cause of death from a single infectious agent. The emergence of multidrug resistance tuberculosis poses a major new threat to the public health, giving new urgency to research aimed at combating this ancient scourge. The development of new strategies to prevent and treat tuberculosis requires more basic knowledge about the key molecules of the organism that allow it to infect the host. One such key molecule is glutamine synthetase. M. tuberculosis glutamine synthetase has three remarkable and very important characteristics, all discovered in the investigator's laboratory during the past three years. First, it is one of the major extracellular proteins and its export by the bacterium is highly correlated with pathogenicity, i.e., pathogenic mycobacteria secrete the enzyme but nonpathogenic mycobacteria do not. Second, its export, which does not involve a signal peptide, is determined by its amino acid sequence, making it an ideal model protein for studying signal peptide-independent protein export. Third, inhibition of its extracellular enzyme activity inhibits its growth both in broth and within human macrophages, making it an extraordinarily accessible and promising target for new antibiotic development. This project has two major goals. First, the investigators seek to use molecular biological approaches to map which amino acids govern the export of M. tuberculosis glutamine synthetase. Second, building upon their studies of a parent compound that inhibits the glutamine synthetase activity and growth of M. tuberculosis and upon their collaborative studies of the high resolution 3-dimensional structure of M. tuberculosis glutamine synthetase, they hope to develop more active entities than the parent compound and thereby to develop a new antibiotic against M. tuberculosis.
