Epigallocatechin gallate, a green tea polyphenol inhibits Mycobacterium smegmatis: In silico and in vitro studies

Abstract

Presence of multidrug resistant strains makes treatment of tuberculosis difficult. Conventional frontline antituberculosis therapy has high incidence of treatment failure due to non-adherence and severe side effects, and therefore warrants alternative approaches using safe, natural compounds. (-) Epigallocatechin gallate, a green tea catechin with significant antimicrobial properties, and its derivatives have been studied for their inhibitory effects on Mycobacterium smegmatis. Enoyl reductase (Inh A, PDB ID: 2NV6), an important drug target inhibited by the antituberculosis drug, isoniazid, was docked with geometrically optimized conformation of epigallocatechin gallate and two of its derivatives using AutoDock software. Perpropionate and permethyl derivatives of epigallocatechin gallate were synthesized and, along with epigallocatechin gallate, evaluated for their inhibitory and cytotoxic properties against M. smegmatis using microplate dilution method and alamarBlue® assay, respectively. Ames test was performed to assess the mutagenic potential of epigallocatechin gallate. It was docked successfully onto the InhA with docking energy of -9.38 kcal mol-1. Analysis of neighbouring groups revealed 11 amino acid residues common to both isoniazid and epigallocatechin gallate. The minimum inhibitory concentrations for epigallocatechin gallate, perpropionate and permethyl were found to be 128 (58.2% inhibition), 8 (32.9%) and 4 (12.5%) μg/ml, respectively. Epigallocatechin gallate showed a cytotoxicity of 18.6% at a concentration of 8 μg/ml, while the two derivatives did not show any toxicity, even at 64 μg/ml. Ames test revealed the absence of mutagenicity for epigallocatechin gallate, in presence and absence of metabolic activation. Non-mutagenic epigallocatechin gallate inhibits the growth of M. smegmatis and warrants further investigation as an adjunct therapy for pathogenic mycobacteria.