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

Matteo Mori (1) , Giovanni Stelitano (2) , Arianna Gelain (1) , Elena Pini (1) , Laurent Chiarelli (2) , José Sammartino (2) , Giulio Poli (3) , Tiziano Tuccinardi (3, 4) , Giangiacomo Beretta (1) , Alessio Porta (2) , Marco Bellinzoni (5) , Stefania Villa (1) , Fiorella Meneghetti (1)

1 UNIMI - Università degli Studi di Milano = University of Milan
2 UNIPV - Università degli Studi di Pavia = University of Pavia
3 University of Pisa - Università di Pisa
4 Temple University [Philadelphia]
5 Microb. Struc. (UMR_3528 / U-Pasteur_5) - Microbiologie structurale - Structural Microbiology

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.

Domains: Chemical Sciences; Cristallography; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Structural Biology [q-bio.BM]; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Computer Science [cs]; Bioinformatics [q-bio.QM]; Physics [physics]; Physics [physics]; Biological Physics [physics.bio-ph]; Life Sciences [q-bio]; Cellular Biology

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⟩