The Prospective Synergy of Antitubercular Drugs With NAD Biosynthesis Inhibitors

Abstract

Given the upsurge of drug-resistant tuberculosis worldwide, there is much focus on developing novel drug combinations allowing shorter treatment duration and a lower toxicity profile. Nicotinamide adenine dinucleotide (NAD) biosynthesis targeting is acknowledged as a promising strategy to combat drug-susceptible, drug-resistant, and latent tuberculosis (TB) infections. In this review, we describe the potential synergy of NAD biosynthesis inhibitors with several TB-drugs in prospective novel combination therapy. Despite not directly targeting the essential NAD cofactor's biosynthesis, several TB prodrugs either require a NAD biosynthesis enzyme to be activated or form a toxic chemical adduct with NAD(H) itself. For example, pyrazinamide requires the action of nicotinamidase (PncA), often referred to as pyrazinamidase, to be converted into its active form. PncA is an essential player in NAD salvage and recycling. Since most pyrazinamide-resistant strains are PncA-defective, a combination with downstream NAD-blocking molecules may enhance pyrazinamide activity and possibly overcome the resistance mechanism. Isoniazid, ethionamide, and delamanid form NAD adducts in their active form, partly perturbing the redox cofactor metabolism. 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. Due to the NAD cofactor's crucial role in cellular energy production, additional synergistic correlations of NAD biosynthesis blockade can be envisioned with bedaquiline and other drugs targeting energy-metabolism in mycobacteria. In conclusion, future strategies targeting NAD metabolism in Mtb should consider its potential synergy with current and other forthcoming TB-drugs.

Keywords: NAD biosynthesis inhibition; delamanid; ethionamide; isoniazid; nicotinamide; pyrazinamide; toxin-antitoxin system; tuberculosis.

Figure 1

Formation of nicotinamide adenine dinucleotide (NAD) chemical adducts by tuberculosis (TB) drugs. Prothionamide, a close chemical analog of ethionamide, undergoes the same transformation. Pretomanid, belonging to the same class of nitroimidazoles as delamanid, may combine with NAD as well. Their structures have been omitted for clarity.

Figure 2

The metabolic interplay between TB drugs and NAD pathways in Mycobacterium tuberculosis. Enzymes (blue) are identified with their gene name, metabolites’ names are in black, and TB drugs or inhibitors are in red. The effects of targeted enzymes’ inhibition/downregulation on bacterial growth or drug efficacy are shown. Green arrows indicate upregulated enzymes upon drug exposure, according to transcriptional analyses. Proteins with available 3D structures are sketched based on their biological quaternary assembly. Enzyme abbreviations: NadB (Rv1595): ASPOX, L-aspartate oxidase; NadA (Rv1594): QSYN, quinolinate synthetase; NadC (Rv1596): QaPRT, quinolinate phosphorybosyltransferase; PncB1 (Rv1330c): NaPRT1, nicotinate phosphoribosyltransferase; PncB2 (Rv0573c): NaPRT1, nicotinate phosphoribosyltransferase; NadD (Rv2421c): NaMNAT, NaMN adenylyltransferase; NadE (Rv2438c): NADS, glutamine-dependent NAD syntetase; PncA (Rv2043c): NMASE, nicotinamide deamidase; PncC (Rv1901): NMND, NMN deamidase; LigA (Rv3014c): NAD-dependent DNA ligase; NudC (Rv3199c): NAD(H) pyrophosphatase; NdhII (Rv1854c); type II NADH:menaquinone oxidoreductase; Sir2/CobB (Rv1151c): NAD-dependent deacetyltransferase. Metabolite abbreviations: NaAD, nicotinic acid adenine dinucleotide; Nam, nicotinamide; Na, nicotinic acid; Qa, quinolinic acid; NaMN, nicotinic acid mononucleotide; NMN, nicotinamide mononucleotide; PRPP, phosphoribosyl diphosphate; PZA, pyrazinamide; POA, pyrazinoic acid; BDQ, bedaquiline; INH, isoniazid; PTN, pretomanid; KCN, potassium cyanide.