Structure based discovery of VMP-7 as a promising GlgE targeting lead against Mycobacterium tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains a major global health challenge, necessitating the identification of novel drug targets with high specificity and therapeutic potential. Maltosyltransferase (GlgE) is a critical enzyme in the biosynthesis of cytosolic α-glucan, a key component required for maintaining cell wall integrity and intracellular survival of the pathogen. GlgE catalyzes the transfer of maltosyl units from maltose-1-phosphate to elongating α-glucan chains, and its inactivation results in toxic accumulation of metabolic intermediates, ultimately leading to bacterial death. Importantly, the absence of homologous pathways in humans underscores its suitability as a selective anti-tubercular (anti-TB) target. Sequence analysis of 382 clinical isolates demonstrated complete conservation of the glgE gene, highlighting its evolutionary stability and essentiality. Subsequently, structure-based virtual screening followed by molecular fingerprint clustering was performed to identify chemically diverse inhibitors. Twelve top ranked compounds (VMP-1 to VMP-12) were further evaluated through in-vitro antimycobacterial assays in broth culture and infected THP-1 derived macrophages, along with cytotoxicity assessment. Among these, VMP-7 exhibited significant inhibitory activity against M.tb at 12.5 μg/mL, with minimal cytotoxic effects on host cells. Collectively, these findings validate GlgE as a highly conserved target and identify VMP-7 as a promising lead candidate for further preclinical development of novel anti-TB therapeutics.