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Mycobacterium tuberculosis (Mtb) depends on the bifunctional enzyme catalase-peroxidase (KatG) for survival within the host. KatG exhibits both catalase and peroxidase activities, serving distinct yet critical roles. While its peroxidase activity is essential for activating the frontline tuberculosis drug isoniazid, its catalase activity protects Mtb from oxidative stress. This bifunctional enzyme is equipped with a unique, protein-derived cofactor, methionine-tyrosine-tryptophan (MYW), which enables catalase activity to efficiently disproportionate hydrogen peroxide in phagocytes. Recent studies reveal that the MYW cofactor naturally exists in a hydroperoxylated form (MYW-OOH) when cell cultures are grown under ambient conditions. New findings highlight a dynamic regulation of KatG activity, wherein the modification of the protein cofactor is removable-from MYW-OOH to MYW-at body temperature or in the presence of micromolar concentrations of hydrogen peroxide. This reversible modification modulates KatG's dual activities: MYW-OOH inhibits catalase activity while enhancing peroxidase activity, demonstrating the chemical accessibility of the cofactor. Such duality positions KatG as a unique target for tuberculosis drug development. Therapeutic strategies that exploit cofactor modification could hold promise, particularly against drug-resistant strains with impaired peroxidase activity. By selectively inhibiting catalase activity, these approaches would render Mtb more vulnerable to oxidative stress while enhancing isoniazid activation-a double-edged strategy for combating tuberculosis.