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Journal articles
Shedding X-ray Light on the Role of Magnesium in the Activity of Mycobacterium tuberculosis Salicylate Synthase (MbtI) for Drug Design
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.
https://hal-pasteur.archives-ouvertes.fr/pasteur-03257004
Contributor : Marie de Tarragon Connect in order to contact the contributor
Submitted on : Thursday, June 10, 2021 - 4:02:36 PM
Last modification on : Thursday, April 14, 2022 - 3:54:03 PM
Long-term archiving on: : Saturday, September 11, 2021 - 7:20:42 PM
Contributor : Marie de Tarragon Connect in order to contact the contributor
Submitted on : Thursday, June 10, 2021 - 4:02:36 PM
Last modification on : Thursday, April 14, 2022 - 3:54:03 PM
Long-term archiving on: : Saturday, September 11, 2021 - 7:20:42 PM
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acs.jmedchem.0c00373.pdf
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Distributed under a Creative Commons Attribution 4.0 International License