Shedding X-ray Light on the Role of Magnesium in the Activity of Mycobacterium tuberculosis Salicylate Synthase (MbtI) for Drug Design - Archive ouverte HAL Access content directly
Journal Articles Journal of Medicinal Chemistry Year : 2020

Shedding X-ray Light on the Role of Magnesium in the Activity of Mycobacterium tuberculosis Salicylate Synthase (MbtI) for Drug Design

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Abstract

The Mg2+-dependent Mycobacterium tuberculosis salicylate synthase (MbtI) 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 structure-activity relationships 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.
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Origin : Publication funded by an institution

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pasteur-03257004 , version 1 (10-06-2021)

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Attribution - CC BY 4.0

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Matteo Mori, Giovanni Stelitano, Arianna Gelain, Elena Pini, Laurent Chiarelli, et al.. Shedding X-ray Light on the Role of Magnesium in the Activity of Mycobacterium tuberculosis Salicylate Synthase (MbtI) for Drug Design. Journal of Medicinal Chemistry, 2020, 63 (13), pp.7066-7080. ⟨10.1021/acs.jmedchem.0c00373⟩. ⟨pasteur-03257004⟩
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