Study of mechanism of interaction of truncated isoniazid-nicotinamide adenine dinucleotide adduct against multiple enzymes of Mycobacterium tuberculosis by a computational approach

ABSTRACT

Objective/Background: Isoniazid [INH] is one of the effective antituberculosis [TB] drugs used for TB treatment. However, most of the drug-resistant Mycobacterium tuberculosis [MTB] clinical strains are resistant to INH, a first-line antituberculous drug. Certain metabolic enzymes such as adenosylhomocysteinase [Rv3248c], universal stress protein [Rv2623], nicotinamide adenine dinucleotide [reduced]-dependent enoyl-acyl carrier protein reductase [Rv1484], oxidoreductase [Rv2971], dihydrofolate reductase [Rv2763c], pyrroline- 5-carboxylate dehydrogenase [Rv1187] have been identified to bind INH-nicotinamide adenine dinucleotide [INH-NAD] and INH-nicotinamide adenine dinucleotide phosphate adducts coupled to Sepharose resin. These enzymes are reported to be involved in many important biochemical processes of MTB, including cysteine and methionine metabolism, mycobacterial growth regulation, mycolic acid biosynthesis, detoxification of toxic metabolites, folate biosynthesis, etc. The truncated INH-nicotinamide adenine dinucleotide [oxidized] adduct, 4-isonicotinoylnicotinamide, isolated from urine samples of human TB patients treated with INH therapy is proposed to have antimycobacterial activity