Ddn-activated metabolites targeting cell wall synthesis and respiratory enzymes

Ddn (Deazaflavin-dependent nitroreductase) is an enzyme in Mycobacterium tuberculosis that activates nitroimidazole prodrugs (e.g., pretomanid, delamanid) by reducing them in a F420-dependent manner to yield reactive metabolites[2][5][6]. These metabolites primarily target cell wall biosynthesis by inhibiting the decaprenylphosphoribose-2'-epimerase complex (DprE1/DprE2), blocking the synthesis of arabinogalactan, a major mycobacterial cell wall component[1]. Additionally, reactive metabolites, in particular nitric oxide, disrupt the respiratory chain (including cytochrome bd oxidase), rapidly depleting intracellular ATP under hypoxic conditions[3]. This dual mechanism underpins the bactericidal action of modern nitroimidazole drugs against both replicating and non-replicating tuberculosis bacteria[1][2][3].

Other names

DdnF420-dependent nitroreductasePA-824 activating enzymedeazaflavin nitroreductase

Prodrug activation: Ddn catalyzes reduction of nitroimidazole prodrugs to reactive metabolites; Cell wall inhibition: Metabolites inhibit DprE1/DprE2, disrupting arabinogalactan/mycolic acid synthesis; Inhibition of respiration: Production of nitric oxide and other reactive species poisons respiratory complexes, such as cytochrome bd oxidase