[ODP7A] a. 抗菌性物質

[ODP-192/WS10-8] 新規抗結核薬デラマニドは抗酸菌内で酸化型NADと付加体を形成する

○西山 晃史¹，林 美佳世²，北本 竜生²，立石 善隆¹，岡 真優子³，西内 由紀子⁴，Xiuhao Chen²，金古 堅太郎⁵，松本 真²，松本 壮吉¹ (¹新潟大院・医歯学総合・細菌，²大塚製薬，³京都府大院・生命環境・食環境安全性，⁴大阪市大院・医・刀根山結核研，⁵新潟大院・自然科学)

Delamanid (DLM), a nitro-dihydroimidazooxazole derivative, has currently been approved for pulmonary multidrug-resistant tuberculosis therapy. DLM is a prodrug activated by mycobacterial F₄₂₀-dependent nitroreductase. However, the active DLM metabolite remained unknown. Comparative LC-MS analysis of DLM metabolites revealed covalent binding of reduced DLM with a nicotinamide ring of NAD derivatives in DLM-treated Mycobacterium tuberculosis var. BCG. Isoniazid-resistant mutations in the type II NADH dehydrogenase gene (ndh) showed higher intracellular NADH/NAD ratio and cross-resistance to DLM, which were restored by complementation of the mutants with wild-type ndh. Our data demonstrated the adduct formation of reduced DLM with NAD in mycobacterial cells and its importance in the action of DLM.