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

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.