Possible Interaction: Isoniazid and NAD

“ABSTRACT One of the most effective and widely used antituberculosis (anti-TB) drugs is isoniazid INH ), a prodrug activated via oxidation that forms an adduct with NAD+ to inhibit NADH-dependent targets of Mycobacterium tuberculosis, such as enoyl-acyl carrier protein reductase (InhA).”

“Our work also revealed the essential roles of nonparenchymal cells, including Kupffer cells and hepatic stellate cells, in the CD38-dependent interactions of NAD+ with INH , leading to the formation of both INH-NAD and AcINH-NAD in the liver.”

“We have further demonstrated that exposure of Isoniazid , Bedaquiline, Rifampicin, and O-floxacin results in higher NADH: NAD+ ratios in the Mtb residing in macrophages.”

“Pyrazinamide and nicotinamide, as well as isoniazid , suppressed the increase of NADase associated with tuberculous infection with the bacilli susceptible to these drugs.”

“Indeed, NAD depletion has been observed in Mycobacterium tuberculosis (Mtb) during isoniazid treatment, and activation of the intracellular NAD phosphorylase MbcT toxin potentiates its effect.”

“As such, INH is an inactive prodrug; it acquires an active conformation by forming an adduct with NAD.”

“It was found that the NAD content and the dry weight of the cells decreased with increasing concentrations of INH.”

“ INH also inhibited both the oxidized nicotinamide adenine dinucleotide ( NAD+ ) and adenosine 5′-monophosphate stimulation of reduced NAD (NADH) oxidase activity associated with the M. phlei and M. tuberculosis H37Ra electron transport particles.”

“Therefore, INH inhibition of regulation and/or stabilization of the electron transport pathway by NAD+ or adenosine 5′-monophosphate may account, in part, for the lethal action of the drug on mycobacteria.”

“There is a decrease in the content of nicotinamide-adenine dinucleotide of tubercle bacilli grown in the presence of isoniazid.”