Role of Superoxide in Catalase-Peroxidase-Mediated Isoniazid Action against Mycobacteria

Isoniazid (INH) activation in vitro is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with O(2) to form an oxyferrous enzyme complex. Since this complex could also form directly via reaction of ferric KatG with superoxide, intracellular activation might be responsive to superoxide concentration. When Mycobacterium smegmatis carrying the M. bovis katG gene was treated with nontoxic levels of plumbagin, a generator of superoxide, the bacteriostatic activity of INH increased unless a plasmid-borne superoxide dismutase gene was also present. Thus, endogenous superoxide probably contributes to intracellular activation of INH.