Adduct Formation of Delamanid with NAD in Mycobacteria.
Mikayo HayashiAkihito NishiyamaRyuki KitamotoYoshitaka TateishiMayuko Osada-OkaYukiko NishiuchiShaban A KabosoXiuhao ChenMamoru FujiwaraYusuke InoueYoshikazu KawanoMasanori KawasakiTohru AbeTsutomu SatoKentaro KanekoKimiko ItohSohkichi MatsumotoMakoto MatsumotoPublished in: Antimicrobial agents and chemotherapy (2020)
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 (F420)-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.
Keyphrases
- mycobacterium tuberculosis
- mass spectrometry
- liquid chromatography
- wild type
- pulmonary tuberculosis
- multidrug resistant
- electron transfer
- induced apoptosis
- signaling pathway
- pulmonary hypertension
- high resolution mass spectrometry
- drug resistant
- high resolution
- ms ms
- stem cells
- drug delivery
- machine learning
- electronic health record
- mesenchymal stem cells
- pseudomonas aeruginosa
- bone marrow
- capillary electrophoresis
- cell therapy
- hiv aids
- artificial intelligence
- binding protein
- cell proliferation
- acinetobacter baumannii
- muscle invasive bladder cancer
- low density lipoprotein
- klebsiella pneumoniae