Phenotypic susceptibility testing of M. tuberculosis against pyrazinamide is technically unreliable compared with testing of other first-line drugs. The genetic basis of most pyrazinamide resistance lies in mutations of which gene, and why does this complicate the assay?

• A rpsL, because streptomycin cross-resistance masks the pyrazinamide endpoint
• B gyrA, because fluoroquinolone exposure selects compensatory pyrazinamide tolerance
• C katG, because isoniazid-resistant strains are invariably pyrazinamide resistant as well
• D pncA, because pyrazinamide acts only at acidic pH, at which bacilli grow poorly in vitro ✓

Explanation

Pyrazinamide is a prodrug converted by the bacterial pyrazinamidase, encoded by pncA, into active pyrazinoic acid, and loss-of-function pncA mutations account for most resistance. The drug is active only at acidic pH around 5.5, yet M. tuberculosis grows poorly at that pH in vitro, making growth-based endpoints difficult to read and yielding frequent false resistance. This explains both the unreliability of phenotypic testing and why pncA sequencing is used as a complementary approach. katG relates to isoniazid and gyrA to fluoroquinolones.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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Written and medically reviewed by the StethoPrep medical team.