From virulence factors to drug development: MbtI as an effective Mycobacterium tuberculosis target

Tuberculosis, the infectious disease caused by M. tuberculosis (Mtb), is still nowadays among the top ten causes of death worldwide, and the first caused by a microorganism. Therefore, the development of novel antitubercular drugs is an urgent need, due to the spread of multi-drug resistant and extensively drug resistant strains. One of the possible strategies to overcome this problem could be the development of novel drugs focusing on virulence factors instead of essential proteins. Iron is an essential cofactor for many Mtb enzymes and it is necessary for the bacterial survival and infection establishment. Mtb chelates the iron from the host thanks to its peculiar siderophores known as mycobactins. MtbI is an enzyme involved in the first step of mycobactin biosynthesis, and it is proved to be an effective druggable target. In our previous studies, we successfully expressed and purified MbtI in recombinant form, and an appropriate fluorometric enzymatic assay was set up. Subsequently, we identified different classes of MbtI inhibitors, among which the phenylfuran-carboxylate structure revealed to be very effective scaffold against this enzyme. However, the potent activity found against the enzymatic activity does not translate in a similar potency against mycobacterial growth. In this work, we report the characterization of novel derivatives, with increased lipophilicity to facilitate the passage through the mycobacterial membrane to reach its target, showing improved antimycobacterial activity thus representing new leads for the development of effective anti-virulence compounds.