Targeting NAD biosynthesis in Mycobacterium tuberculosis

Emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), represents a major threat to TB control. There is an urgent need for development of new and more effective anti-tubercular drugs targeting previously unexplored cellular processes. The goal of this proposal is to find a novel class of antimicrobial compounds active against Mtb. Nicotinamide mononucleotide adenylyltransferase (NadD), an essential enzyme of NAD biosynthesis, represents a highly promising target for drug development against bacterial pathogens. In recent years there have been a number of NadD inhibitors developed and validated against Escherichia coli, Bacillus subtilis and B. anthracis. Published data indicate that NadD is required for the growth and survival of mycobacteria. Thus, this recent progress provides a starting point for pursuing this enzyme as a target for the development of novel anti-tubercular drugs. The experiments in this proposal are designed to find inhibitors of Mtb NadD using a combination of structural biology approach and our recently developed virtual screening (VS) methodology. We propose to use our crystal structure of Mtb NadD and previously identified scaffolds active against E. coli and B. anthracis NadD, to apply an iterative ligand- and structure-based VS approach to discover the NadD inhibitors with submicromolar IC50. The VS method will exploit databases with approved drugs that have already been shown to be safe in humans. Upon successful completion of this project we will obtain a number of potent and safe lead compounds that would be further validated in in vivo studies. The strategies developed in the proposed study will be also applicable to other medically relevant targets.