[ODP7A] a. Antimicrobial Agents

[ODP-192/WS10-8] Adduct formation of delamanid with NAD in mycobacteria

○Akihito Nishiyama¹, Mikayo Hayashi², Ryuki Kitamoto², Yoshitaka Tateishi¹, Mayuko Osada-Oka³, Yukiko Nishiuchi⁴, Xiuhao Chen², Kentaro Kaneko⁵, Makoto Matsumoto², Sohkichi Matsumoto¹ (¹Dept. Bacteriol., Sch. Med., Niigata Univ., ²Pharm. Bus. Div., Otsuka Pharmaceutical Co., Ltd., ³Div. Applied Life Sci., Grad. Sch. Life Environ. Sci., Kyoto Prefect. Univ., ⁴Toneyama Ins. for Tuberculosis Res., Med. Sch., Osaka City Univ., ⁵Grad. Sch. Sci. Technol., Niigata Univ.)

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.