Pyrazinamide is most active at acidic pH and kills intracellular mycobacteria. Its mechanism of action after conversion to pyrazinoic acid involves inhibition of which target?

• A Mycobacterial fatty acid synthase I (FAS-I), disrupting cell wall mycolic acid synthesis
• B Mycobacterial RNA polymerase beta subunit, blocking transcription
• C Mycobacterial topoisomerase II (DNA gyrase), impairing DNA replication
• D Mycobacterial ribosomal protein S1 (RpsA), impairing trans-translation ✓

Explanation

Pyrazinamide is a prodrug converted to pyrazinoic acid (POA) by mycobacterial pyrazinamidase (PncA). POA primarily inhibits the ribosomal protein S1 (RpsA), which is essential for trans-translation — a rescue mechanism that releases stalled ribosomes. POA also inhibits fatty acid synthase I, but inhibition of RpsA is now recognized as the key lethal mechanism. Mutations in pncA (preventing POA formation) are the most common mechanism of pyrazinamide resistance.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.