Adduct Formation of Delamanid with NAD in Mycobacteria
Mikayo Hayashi, Akihito Nishiyama, Ryuki Kitamoto, Yoshitaka Tateishi, Mayuko Osada‐Oka, Yukiko Nishiuchi, Shaban A. Kaboso, Xiuhao Chen, et al. (18 authors)
Antimicrobial Agents and Chemotherapy · 2020-03
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 (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.
MeSH terms
- Nitroreductase
- NAD+ kinase
- Prodrug
- Cofactor
- Biochemistry
- Metabolite
- Nicotinamide
- Mycobacterium tuberculosis
- Mycobacterium
- Adduct
- Chemistry
- Biotransformation
- Biology
- Stereochemistry
- Enzyme