Pretomanid, used in the BPaL regimen for extensively drug-resistant TB, is a nitroimidazole that acts by a mechanism involving:
- A Inhibition of mycobacterial InhA (enoyl-ACP reductase) after activation by mycobacterial catalase-peroxidase KatG
- B Reductive activation by deazaflavin-dependent nitroreductase (Ddn) in mycobacteria generates reactive nitrogen intermediates that inhibit ketomycolate synthesis (active bacilli) and deplete ATP via respiratory poisoning (non-replicating anaerobic bacilli) ✓
- C Blocking of mycobacterial arabinosyl transferases (EmbA, EmbB, EmbC), disrupting arabinogalactan synthesis in the cell wall
- D Inhibition of mycobacterial DNA-directed RNA polymerase beta subunit (rpoB), preventing transcription
Explanation
Pretomanid (a bicyclic nitroimidazole) requires reductive activation by mycobacterial F420-dependent nitroreductase (encoded by Ddn). Under aerobic conditions, the activated species inhibits the synthesis of hydroxymycolates (ketomycolates) — key components of the mycobacterial cell wall. Uniquely, under anaerobic conditions (non-replicating/latent bacilli), the activation generates reactive nitrogen intermediates (NO, reactive nitrogen species) that poison the electron transport chain, depleting ATP in dormant organisms. This dual activity against both replicating and non-replicating bacilli makes pretomanid valuable in the BPaL regimen (Bedaquiline + Pretomanid + Linezolid) for XDR-TB and treatment-intolerant MDR-TB.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.