Shedding X-ray light on the role of magnesium in the activity of M. tuberculosis salicylate synthase (MbtI) for drug design
Articolo
Data di Pubblicazione:
2020
Citazione:
Shedding X-ray light on the role of magnesium in the activity of M. tuberculosis salicylate synthase (MbtI) for drug design / M. Mori, G. Stelitano, A. Gelain, E. Pini, L.R. Chiarelli, J.C. Sammartino, G. Poli, T. Tuccinardi, G. Beretta, A. Porta, M. Bellinzoni, S. Villa, F. Meneghetti. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 63:13(2020 Jul 09), pp. 7066-7080. [10.1021/acs.jmedchem.0c00373]
Abstract:
The Mg2+-dependent salicylate synthase (MbtI) from Mycobacterium tuberculosis is a key enzyme involved in the biosynthesis of siderophores. Because iron is essential for the survival and pathogenicity of the microorganism, this protein constitutes an attractive target for antitubercular therapy, also considering the absence of homologous enzymes in mammals. An extension of the SAR of our furan-based candidates allowed us to disclose the most potent competitive inhibitor known to date (10, Ki = 4 μM), which also proved effective on mycobacterial cultures. By structural studies, we characterized its unexpected Mg2+-independent binding mode. We also investigated the role of the Mg2+ cofactor in catalysis, analyzing the first crystal structure of the MbtI-Mg2+-salicylate ternary complex. Overall, these results pave the way for the development of novel antituberculars through the rational design of improved MbtI inhibitors.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Tuberculosis; magnesium; divalent cations; antitubercular agents; MST enzymes; catalytic mechanism; siderophores; X-ray crystal structures; mycobactins; MbtI conformations.
Elenco autori:
M. Mori, G. Stelitano, A. Gelain, E. Pini, L.R. Chiarelli, J.C. Sammartino, G. Poli, T. Tuccinardi, G. Beretta, A. Porta, M. Bellinzoni, S. Villa, F. Meneghetti
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