What is the mechanism of action of Delamanid?

Delamanid(Delamanid) is a newer inhibitor of mycobacterial cell wall synthesis that has received conditional approval from the European Medicines Agency (EMA) for the treatment of MDR-TB. Preclinical and clinical studies have shown that Delamanid has greater potency, minimal risk of drug interactions and better tolerability.

Delamanid is a prodrug that requires biotransformation by the mycobacterialF420coenzyme system, including deazoflavin-dependent nitroreductase(Rv3547), to mediate its antimycobacterial activity against growing and non-growing mycobacteria. Five coenzymesF420genes(fgd, Rv3547, fbiA, fbiB and fbiC) are thought to be mechanisms of resistance to delamanid. Upon activation, the free radical intermediate formed between deramosamine and denitroimidazole derivatives is thought to mediate the antimycobacterial effect by inhibiting the synthesis of methoxymycolic acids and ketomycolic acids, leading to the depletion of mycobacterial cell wall components and the destruction of mycobacteria. Nitroimidazoxazole derivatives are thought to generate reactive nitrogen species, including nitrogen oxides(NO). However, unlike isoniazid, delamanid does not contain α-mycolic acid.

Delamaniworks by blocking the production of methoxy and ketomycolic acids and the production of nitrous oxide through the mycobacterialF420pathway. It works by blocking the formation of mycolic acid, which is required for the survival of mycobacteria, it requires activation of the mycobacterialF420system.

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