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

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

Answer: (A)