Question

Pretomanid, a nitroimidazole used in the BPaL/BPaLM regimen for drug-resistant tuberculosis, acts mainly by which mechanism?

• A. Inhibition of mycolic acid synthesis (and generation of reactive nitrogen species), impairing cell-wall formation and anaerobic respiration
• B. Inhibition of the RNA polymerase beta-subunit (rpoB)
• C. Inhibition of mycobacterial ATP synthase
• D. Inhibition of DNA gyrase (topoisomerase II)

Hint:

A nitroimidazole prodrug activated by Ddn that blocks cell-wall (mycolic acid) synthesis.

Answer 1

The Correct Option is A

Step 1: Classify the drug.
Pretomanid (PA-824) is a nitroimidazo-oxazine prodrug, structurally related to delamanid. It is activated inside Mycobacterium tuberculosis by the deazaflavin (F420)-dependent nitroreductase (Ddn), which requires the cofactor F420 generated by the fgd1/fbiABC pathway.

Step 2: Mechanism of action.
Once activated, pretomanid has a dual action. Against actively replicating (aerobic) bacilli it inhibits the synthesis of mycolic acids, key components of the mycobacterial cell wall, by blocking oxidation of hydroxymycolate to ketomycolate. Against non-replicating (anaerobic/dormant) bacilli, its reductive activation releases reactive nitrogen species, including nitric oxide, which poison the respiratory chain and exert anaerobic killing.

Step 3: Why the other options are wrong.
RNA polymerase (rpoB) inhibition is the mechanism of rifampicin. ATP synthase inhibition is the mechanism of bedaquiline (the "B" in BPaL). DNA gyrase inhibition is the mechanism of fluoroquinolones such as moxifloxacin/levofloxacin.

Key fact: Pretomanid inhibits mycolic acid/cell-wall synthesis and releases reactive nitrogen species, killing both replicating and dormant M. tuberculosis.