Adduct Formation of Delamanid with NAD in Mycobacteria.

Abstract

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.

• Authors: Mikayo Hayashi, Akihito Nishiyama, Ryuki Kitamoto, Yoshitaka Tateishi, Mayuko Osada-Oka, Yukiko Nishiuchi, Shaban A Kaboso, Xiuhao Chen, Mamoru Fujiwara, Yusuke Inoue, Yoshikazu Kawano, Masanori Kawasaki, Tohru Abe, Tsutomu Sato, Kentaro Kaneko, Kimiko Itoh, Sohkichi Matsumoto, Makoto Matsumoto
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 64 Issue 5 (04 21 2020) ISSN: 1098-6596 [Electronic] United States
• PMID: 32152081 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 American Society for Microbiology.

Chemical References

• Antitubercular Agents
• Mycolic Acids
• Nitroimidazoles
• OPC-67683
• Oxazoles
• NAD
• NADH dehydrogenase II
• NADH Dehydrogenase
• Isoniazid

Topics

• Antitubercular Agents (pharmacology)
• Chromatography, Liquid
• Drug Resistance, Multiple, Bacterial (genetics)
• Isoniazid (pharmacology)
• Mass Spectrometry
• Mycobacterium tuberculosis (drug effects, genetics)
• Mycolic Acids (metabolism)
• NAD (analysis)
• NADH Dehydrogenase (genetics)
• Nitroimidazoles (pharmacology)
• Oxazoles (pharmacology)
• Oxidation-Reduction
• Polymorphism, Single Nucleotide (genetics)
• Tuberculosis, Multidrug-Resistant (drug therapy, genetics)
• Tuberculosis, Pulmonary (drug therapy)