Tuberculosis (TB) continues to be a major cause of morbidity and mortality worldwide. The increasing emergence and spread of
drug-resistant TB poses a significant threat to disease control and calls for the urgent development of new drugs. The
tryptophan biosynthetic pathway plays an important role in the survival of Mycobacterium tuberculosis. Thus,
indole-3-glycerol phosphate synthase (IGPS), as an essential
enzyme in this pathway, might be a potential target for anti-TB
drug design. In this study, we deduced the structure of IGPS of M.
tuberculosis H37Rv by using homology modeling. On the basis of this deduced IGPS structure, screening was performed in a search for novel inhibitors, using the Maybridge database containing the structures of 60,000 compounds.
ATB107 was identified as a potential binding molecule; it was tested, and shown to have antimycobacterial activity in vitro not only against the laboratory strain M.
tuberculosis H37Rv, but also against clinical isolates of multidrug-resistant TB strains. Most MDR-TB strains tested were susceptible to 1 microg x mL(-1)
ATB107.
ATB107 had little toxicity against THP-1 macrophage cells, which are human monocytic
leukemia cells.
ATB107, which bound tightly to IGPS in vitro, was found to be a potent competitive inhibitor of the substrate 1-(o-carboxyphenylamino)-1-deoxyribulose-5'-phosphate, as shown by an increased K(m) value in the presence of
ATB107. The results of site-directed mutagenesis studies indicate that
ATB107 might inhibit IGPS activity by reducing the binding affinity for substrate of residues Glu168 and Asn189. These results suggest that
ATB107 is a novel potent inhibitor of IGPS, and that IGPS might be a potential target for the development of new anti-TB drugs. Further evaluation of
ATB107 in animal studies is warranted.