Deazaflavin-dependent nitroreductase (Ddn) (Ddn)

Deazaflavin-dependent nitroreductase (Ddn) is a specialized enzyme in Mycobacterium tuberculosis that utilizes the unique deazaflavin cofactor F420 to catalyze the reduction of nitroaromatic compounds. While its endogenous physiological role is linked to redox balance and potentially the detoxification of reactive carbonyls, it is most notable in pharmacology as the essential activator for the bicyclic nitroimidazole class of antitubercular drugs, such as Pretomanid and Delamanid. Upon binding these prodrugs, Ddn facilitates their reduction to generate reactive intermediates and nitric oxide, which subsequently disrupt the synthesis of mycolic acids—critical components of the mycobacterial cell wall—and interfere with respiratory metabolism. This dual mechanism allows the targeting of both actively growing and dormant (hypoxic) bacilli, making the Ddn-mediated pathway a cornerstone of modern multidrug-resistant tuberculosis (MDR-TB) treatment regimens. Mutations in the ddn gene or the biosynthetic pathway of its F420 cofactor are the primary drivers of clinical resistance to nitroimidazole-based therapies.

Other names

F420-dependent nitroreductaseDeazaflavin-dependent oxidoreductaseRv3547F420-dependent mycolic acid synthesis inhibitor activator

Ddn acts as a prodrug activator that reduces nitroimidazole compounds (Pretomanid and Delamanid) using reduced cofactor F420 (F420H2). This reduction releases reactive nitrogen species, including nitric oxide (NO), which inhibits mycolic acid biosynthesis and cellular respiration, leading to bacterial cell death in both replicating and non-replicating Mycobacterium tuberculosis.