A novel inhibitor of indole-3-glycerol phosphate synthase with activity against multidrug-resistant Mycobacterium tuberculosis.
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.
Shen
Hongbo
H
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
Wang
Feifei
F
Zhang
Ying
Y
Huang
Qiang
Q
Xu
Shengfeng
S
Hu
Hairong
H
Yue
Jun
J
Wang
Honghai
H
D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007209:Indole-3-Glycerol-Phosphate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009163:Mycobacterium bovis / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011812:Quinuclidines / Q000494:pharmacology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D016963:Thermus thermophilus / Q000201:enzymology*; D014227:Triazines / Q000494:pharmacology*
C534782:ATB 107; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011812:Quinuclidines; D014227:Triazines; D007209:Indole-3-Glycerol-Phosphate Synthase