New inhibitors of salicylate synthase (MbtI) from m. tubercolosis: a promising strategy to antitubercular drugs

Tuberculosis nowadays ranks as the second leading cause of death from an infectious disease worldwide. In the last twenty years, this disease has again started to spread mainly for the appearance of multi-drug resistant forms. Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis (Mtb), because it serves as cofactor in many essential biological processes, including DNA biosynthesis and cellular respiration. Given the high toxicity of the free iron, Mtb synthesizes chelating agents, called siderophores, to assimilate it. In particular, the cell associated and soluble mycobactins play an important role. Therefore, mycobactin biosynthesis has been identified as an attractive target to develop new agents to treat tuberculosis, especially the multidrug resistant infections. This new project aims at the design, synthesis, characterization and biological evaluation of mechanism based inhibitors of the salicylate synthase (MbtI) which catalyzes the first essential step in mycobactin biosynthesis. Preliminary molecular modeling experiments based on the crystallographic protein structure suggest a pharmacophore-based receptor model.By means of the consensus docking approach a selected commercial database of compounds was filtered, and two hits emerged as interesting for development. The synthesis, the molecular modeling and the biological results of the prepared hits derivatives will be presented in the poster. These results could lead to the disclosure of new drug candidates acting on a specific bacterial target absent inhumans.