Introduction
The development of drug resistance is a severe threat to public health. Presently, use of antibiotics targets bacterial structure and essential functions. Due to the well-identified anti-mycobacterial resistance, there has been an increased interest in the discovery of novel drugs to target other essential processes of bacterial survival. Currently, target-based drug screening is promising and efficient way for development of therapeutic agents. In recent years, extensive efforts have been made for the discovery of inhibitors of enzymes involved in the biosynthesis of aromatic amino acids. One such well-recognised pathway is shikimic acid pathway consisting of seven enzymatic reactions responsible for the production of chorismate; a precursor for essential amino acids. Among seven enzymes, the most valuable target is Shikimate Kinase (SK). Inhibition of this enzyme is fatal for M. tuberculosis (Mtb ).1 SK inhibitors offer potential for development of new anti-tubercular drugs that are selective for Mtb since mammals do not have Shikimate pathway enzymes necessary for de novo synthesis of essential amino acids. MTSK belongs to the family of nucleoside monophosphate (NMP) kinases and consist of 3 domains: LID (LD), CORE (CD), and substrate binding (SBD) domains.2, 3
Owing to the importance of this enzyme, structural based virtual screening of compounds from institute library was done where S-014-1049 was found to be active against SK and against the mycobacteria in culture as well. This compound specifically binds to the CD of the enzyme which was primarily confirmed during the docking studies and further by validating with the mutants.It is a polyphenol and derivative of curcumin. In some recent studies a few polyphenols were found active against Mtb which also have many health benefits.4 The biological and pharmacological properties make polyphenols a valuable druggable molecule .5, 6 In one of our previous studies, we found an existing polyphenolic PKC-δ inhibitor, Rottlerin to be active against mycobacteria where it significantly inhibited SK activity and has been used as positive control in this study.7Therefore, compound S-014-1049 could be a promising drug candidate for further development