A patient with MDR-TB is started on pretomanid (Pa) as part of the BPaL regimen. Pretomanid's mechanism of action against M. tuberculosis involves:

• A Inhibiting the DprE1 enzyme (decaprenylphosphoryl-beta-D-ribose oxidase) in the arabinan biosynthesis pathway
• B Dual action: bioreductive activation generating reactive nitrogen intermediates (RNI) disrupting F420 metabolism and inhibiting cell wall mycolic acid synthesis via inhibition of hydroxymycolate production ✓
• C Binding the beta-subunit of RNA polymerase at a site distinct from rifampicin's binding site
• D Inhibiting ATP synthase subunit c (atpE) similar to bedaquiline but with additional ROS generation

Explanation

Pretomanid is a nitroimidazole that requires bioreductive activation by M. tuberculosis Rv3547 (deazaflavin F420-dependent nitroreductase Ddn). Under anaerobic conditions, activation generates reactive nitrogen intermediates (NO and RNS) causing respiratory tract damage. Under aerobic conditions, it inhibits the final step of mycolic acid biosynthesis (inhibiting hydroxymycolate conversion). This dual aerobic/anaerobic activity against both replicating and non-replicating persistent bacilli makes it valuable in XDR/MDR-TB. DprE1 inhibition is the mechanism of delamanid (another nitroimidazole) and TBA-354. Bedaquiline inhibits ATP synthase.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.