Devise a rationale explaining why isoniazid resistance often results from mutations in katG (encoding a bacterial catalase-peroxidase) and how that affects therapy design.

Isoniazid is a prodrug requiring activation by bacterial catalase-peroxidase (KatG); mutations reducing KatG activity prevent conversion to the active form, causing resistance—this necessitates use of alternative or additional antitubercular drugs that do not rely on KatG activation.

KatG mutations increase production of mycolic acids so isoniazid is overwhelmed by excess substrate; the correct clinical response is to increase isoniazid dose tenfold without changing the drug regimen.

KatG mutations change the host immune response allowing Mycobacterium to hide intracellularly; thus, the solution is to stop antibiotics and rely on immunomodulation alone.

KatG directly pumps isoniazid into the cell interior; mutations enhance this pumping leading to intracellular drug accumulation which paradoxically decreases efficacy and mandates switching to topical therapy only.