The 94th Annual Meeting of Japanese Society for Bacteriology

Presentation information

Workshop

[WS10] Selected from Oral Session: Antimicrobials and Drug Resistance

Thu. Mar 25, 2021 12:45 PM - 2:45 PM Channel 4

Conveners: Hironobu Nakayama (Suzuka University of Medical Science), Kunihiko Nishino (The Institute of Scientific and Industrial Research, Osaka Univ.)

[WS10-8/ODP-192] 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.