This patient with HIV has fever, headache, vomiting, and cerebrospinal fluid analysis results consistent with tuberculous meningitis.  Cultures reveal the isolate has reduced activity of intracellular catalase-peroxidase, indicating the organism is likely resistant to isoniazid (INH).

INH inhibits the synthesis of mycolic acid, a crucial lipid component of the mycobacterial cell wall.  Reductions in mycolic acid availability impair cell wall development, leading to a bactericidal effect.  However, INH is only active once it is processed by mycobacterial catalase-peroxidase.  Therefore, mycobacteria can limit the effect of INH by reducing intracellular levels of catalase-peroxidase.  Other common mechanisms of INH resistance are alteration in the target enzyme binding site and overexpression of the target enzyme.

(Choice A)  Ethambutol likely inhibits synthesis of the mycobacterial cell wall.  Resistance develops when the mycobacteria increase production of arabinosyl transferase (an enzyme in the pathway to arabinogalactan, a key constituent of the mycobacterial cell wall).

(Choice C)  Because pyrazinamide must be converted to an active form by the mycobacterial enzyme pyrazinamidase, drug resistance can occur when pyrazinamidase is altered or eliminated.

(Choice D)  Resistance to rifampin is primarily due to a mutation in the gene that codes for a DNA-dependent RNA polymerase necessary for transcription and RNA elongation.

(Choice E)  Streptomycin (used in some patients with tuberculosis) is an aminoglycoside that inhibits mycobacterial protein synthesis by disabling the bacterial ribosomal 30S subunit (which disrupts translation).  Resistance to this drug is primarily achieved by a modification of the 30S ribosomal protein.

Educational objective:
Mycobacterial resistance to isoniazid (INH) is primarily mediated by reductions in the catalase-peroxidase enzyme or through genetic modification of the INH binding site on the mycolic acid synthesis enzyme.