Pretomanid, used in the BPaL regimen for XDR-TB, has a novel mechanism. Which statement best describes its mechanism and why it is effective against non-replicating (dormant) mycobacteria?

• A Pretomanid is a direct inhibitor of InhA (enoyl-ACP reductase) in mycolic acid synthesis, similar to isoniazid but not requiring activation by KatG
• B Pretomanid inhibits DprE1 (decaprenylphosphoryl-β-D-ribose-2-epimerase) in arabinogalactan synthesis, the same target as bedaquiline
• C Pretomanid is a fatty acid synthase-I inhibitor that blocks de novo lipid synthesis in replicating mycobacteria only
• D Pretomanid is a nitroimidazole prodrug activated by Mycobacterium's deazaflavin-dependent nitroreductase (Ddn), generating reactive nitrogen and carbon species that damage the cell membrane and inhibit cell wall lipid synthesis — active against both aerobic replicating and anaerobic non-replicating bacteria ✓

Explanation

Pretomanid (PA-824) is a bicyclic nitroimidazole prodrug from the nitroimidazooxazine class. It requires activation by an NADH-dependent deazaflavin (F420)-dependent nitroreductase (Ddn, encoded by Rv3547) within M. tuberculosis. The activated compound releases reactive nitrogen species (RNS) including nitric oxide (NO) and nitrous acid, which damage multiple cellular targets, particularly mycobacterial cell membrane lipids and proteins. Under anaerobic conditions (simulating the environment of dormant bacteria within granulomas), pretomanid additionally releases carbon-based reactive species that inhibit mycolic acid biosynthesis. This dual mode of action allows pretomanid to kill both aerobically replicating and anaerobically non-replicating (dormant/persister) bacilli — addressing a major limitation of conventional TB drugs. In the ZeNix trial, BPaL (bedaquiline-pretomanid-linezolid) achieved 89% culture conversion in XDR/pre-XDR TB at 26 weeks.

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

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Written and medically reviewed by the StethoPrep medical team.