Structural insights for the development of novel antituberculars targeting the iron uptake pathway

Tuberculosis nowadays ranks among the leading causes of death worldwide, and the growing emergence of resistant strains of Mycobacterium tuberculosis (Mtb) poses a serious threat to the public\u2019s health; therefore, the discovery of new antitubercular agents is assuming critical importance. In this context, the inhibition of the mycobacterium-specific salicylate synthase MbtI, which is involved in the iron uptake pathway, has been recently validated as a pharmacological target for the development of novel antitubercular agents. A structure-based virtual screening allowed us to identify a competitive furan-based inhibitor of MbtI (VS1, IC50 = 21.1 \u3bcM). With the aim of increasing its inhibitory effect, we explored the chemical space around this hit through a thorough structure-activity relationship study, leading to the identification of more potent MbtI inhibitors. These compounds exhibited a promising antimycobacterial action, related to the reduced production of siderophores. The novel lead compounds were submitted to co-crystallization experiments to empirically define the binding mode of this class of compounds within the active site of MbtI. The structural data allowed us to evidence the interactions of the inhibitors at a molecular level, revealing previously undetermined roles of key residues. These results may lead to the identification of new strategies for rational modifications intended to improve the inhibitory properties of the molecules