Adduct Formation of Delamanid with NAD in Mycobacteria
| Autor: | Akihito Nishiyama, Makoto Matsumoto, Tohru Abe, Sohkichi Matsumoto, Kimiko Itoh, Yoshitaka Tateishi, Shaban A. Kaboso, Tsutomu Sato, Ryuki Kitamoto, Xiuhao Chen, Kentaro Kaneko, Yusuke Inoue, Mikayo Hayashi, Mayuko Osada-Oka, Yoshikazu Kawano, Mamoru Fujiwara, Yukiko Nishiuchi, Masanori Kawasaki |
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| Rok vydání: | 2019 |
| Předmět: |
Antitubercular Agents
Polymorphism Single Nucleotide Cofactor Mass Spectrometry 03 medical and health sciences chemistry.chemical_compound Nitroreductase Drug Resistance Multiple Bacterial Tuberculosis Multidrug-Resistant medicine Isoniazid Pharmacology (medical) Oxazoles Tuberculosis Pulmonary Mechanisms of Action: Physiological Effects 030304 developmental biology Pharmacology 0303 health sciences Nicotinamide biology 030306 microbiology NADH dehydrogenase NADH Dehydrogenase Mycobacterium tuberculosis Prodrug biology.organism_classification NAD Infectious Diseases chemistry Biochemistry Mycolic Acids Nitroimidazoles biology.protein NAD+ kinase Delamanid Oxidation-Reduction medicine.drug Mycobacterium Chromatography Liquid |
| Zdroj: | Antimicrob Agents Chemother |
| ISSN: | 1098-6596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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