第94回日本細菌学会総会

講演情報

オンデマンド口頭発表(ODP)

7 抗菌性物質と薬剤耐性

[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.