Open AccessAdduct Formation of Delamanid with NAD in Mycobacteria
Author(s) -
Mikayo Hayashi,
Akihito Nishiyama,
Ryuki Kitamoto,
Yoshitaka Tateishi,
Mayuko OsadaOka,
Yukiko Nishiuchi,
Shaban A. Kaboso,
Xiuhao Chen,
M̄. Fujiwara,
Yusuke Inoue,
Yoshikazu Kawano,
Masanori Kawasaki,
Tohru Abe,
Tsutomu Sato,
Kentaro Kikuchi,
Kazuyoshi Itoh,
Sohkichi Matsumoto,
Makoto Matsumoto
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01755-19
Subject(s) - nitroreductase , nad+ kinase , prodrug , cofactor , nicotinamide , metabolite , biochemistry , biotransformation , mycobacterium tuberculosis , chemistry , mycobacterium , biology , enzyme , microbiology and biotechnology , tuberculosis , bacteria , medicine , pathology , genetics
Delamanid (DLM), a nitro-dihydroimidazooxazole derivative currently approved for pulmonary multidrug-resistant tuberculosis (TB) therapy, is a prodrug activated by mycobacterial 7,8-didemethyl-8-hydroxy 5-deazaflavin electron transfer coenzyme (F 420 )-dependent nitroreductase (Ddn). Despite inhibiting the biosynthesis of a subclass of mycolic acids, the active DLM metabolite remained unknown. Comparative liquid chromatography-mass spectrometry (LC-MS) analysis of DLM metabolites revealed covalent binding of reduced DLM with a nicotinamide ring of NAD derivatives (oxidized form) in DLM-treated Mycobacterium tuberculosis var. Bacille de Calmette et Guérin. Isoniazid-resistant mutations in the type II NADH dehydrogenase gene ( ndh ) showed a 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 for the first time the adduct formation of reduced DLM with NAD in mycobacterial cells and its importance in the action of DLM.