TARGETING THE MYCOBACTERIAL SHIELD: MECHANISMS OF ANTIMYCOBACTERIAL ACTION OF PLANT METABOLITES INHIBITING THE Rv2349c (PlcC) GENE IN MYCOBACTERIUM TUBERCULOSIS

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major infectious threat compounded by multidrug resistance. Modern drug discovery increasingly targets bacterial virulence mechanisms enabling intracellular survival. The Rv2349c gene encodes phospholipase C (PlcC), a zinc-dependent esterase essential for hydrolyzing host membrane phospholipids (phosphatidylcholine and sphingomyelin), thereby mediating phagosomal escape and macrophage death.

This study evaluates plant metabolites—monoterpenes (thymol, carvacrol, eugenol, 1,8-cineole) and polyphenols (curcumin, quercetin)—as enzymatic inhibitors of PlcC. Integrated in silico molecular docking, enzymatic assays, and macrophage survival models demonstrate that these phytocompound scaffolds bind to the catalytic zinc pocket and entry cleft of PlcC (binding free energies -7.2 to -9.4 kcal/mol). Inhibition preserves phagosomal integrity, arrests bacilli within acidifying phagolysosomes, and repolarizes macrophages to an antibacterial M1 phenotype. Co-administration with rifampicin restores intracellular drug susceptibility, establishing plant secondary metabolites as promising adjunctive therapeutics.