INHIBITORS OF GLUTAMINE SYNTHETASE FROM SALMONELLA TYPHIMURIUM AND MYCOBACTERIUM TUBERCULOSIS. Harindarpal Gill, Gunter Harth, Marcus Horwitz, David Eisenberg, Molecular Biology Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles. Los Angeles, California, 90095-1570, USA

Tuberculosis has re-emerged as a global health concern-- causing 8 million new cases of pulmonary tuberculosis and 3 million deaths annually. Existing drugs are becoming less effective because of a rise in anti-Mycobacterial resistance. Discovery of novel drug targets are complicated by the need to penetrate the thick cellular envelope of Mycobacteria. However, recently it has been discovered that pathogenic Mycobacteria (tuberculosis and bovis) secrete enzymes into their immediate environment. In particular, Glutamine Synthetase (GS) is secreted into the medium where it is thought to play a role in the synthesis of poly-(L-glutamine-L-glutamate) chains which are a constituent of pathogenic Mycobacteria cell walls.

This secreted GS is our primary target for drug-design. Bacterial GS is a dodecamer with 12 separate active sites, one each between a pair of subunits. In contrast, eukaryotic GS is an octamer implying that the pockets that form each active site in human GS must be significantly different than bacterial GS, thus allowing for drug-specificity. Two inhibitors-- methionine sulfoximine (MetSox) and phosphinothricin (PPT)-- are potent inhibitors of GS. Preliminary results from these inhibitors demonstrate a static inhibition on the Mycobacterium tuberculosis (TB) growth curve. Efforts are underway to co-crystallize these inhibitors with GS from Salmonella typhimurium in hope to obtain a high resolution structure which might serve as a better model for computational drug- design. Future studies of this kind are planned with TB-GS and other studies involving fully-adenylylated GS are being pursued.