Targeting NAD biosynthesis in bacterial pathogens: Structure-based development of inhibitors of nicotinate mononucleotide adenylyltransferase NadD

Chem Biol. 2009 Aug 28;16(8):849-61. doi: 10.1016/j.chembiol.2009.07.006.


The emergence of multidrug-resistant pathogens necessitates the search for new antibiotics acting on previously unexplored targets. Nicotinate mononucleotide adenylyltransferase of the NadD family, an essential enzyme of NAD biosynthesis in most bacteria, was selected as a target for structure-based inhibitor development. Using iterative in silico and in vitro screens, we identified small molecule compounds that efficiently inhibited target enzymes from Escherichia coli (ecNadD) and Bacillus anthracis (baNadD) but had no effect on functionally equivalent human enzymes. On-target antibacterial activity was demonstrated for some of the selected inhibitors. A 3D structure of baNadD was solved in complex with one of these inhibitors (3_02), providing mechanistic insights and guidelines for further improvement. Most importantly, the results of this study help validate NadD as a target for the development of antibacterial agents with potential broad-spectrum activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Bacillus anthracis / enzymology
  • Binding Sites
  • Computational Biology
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / enzymology
  • Kinetics
  • NAD / biosynthesis*
  • NAD / chemistry
  • Nicotinamide-Nucleotide Adenylyltransferase / antagonists & inhibitors*
  • Nicotinamide-Nucleotide Adenylyltransferase / metabolism
  • Protein Structure, Tertiary


  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • NAD
  • Nicotinamide-Nucleotide Adenylyltransferase
  • nicotinic acid mononucleotide adenylyltransferase

Associated data

  • PDB/3E27
  • PDB/3HFJ