Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA

Nat Chem Biol. 2014 Feb;10(2):96-8. doi: 10.1038/nchembio.1405. Epub 2013 Dec 1.


Pyridomycin, a natural product with potent antituberculosis activity, inhibits a major drug target, the InhA enoyl reductase. Here, we unveil the co-crystal structure and unique ability of pyridomycin to block both the NADH cofactor- and lipid substrate-binding pockets of InhA. This is to our knowledge a first-of-a-kind binding mode that discloses a new means of InhA inhibition. Proof-of-principle studies show how structure-assisted drug design can improve the activity of new pyridomycin derivatives.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemistry*
  • Bacterial Proteins / chemistry*
  • Binding Sites
  • Crystallography, X-Ray
  • Models, Molecular
  • NAD / chemistry*
  • Oligopeptides / chemistry*
  • Oxidoreductases / chemistry*
  • Substrate Specificity


  • Antitubercular Agents
  • Bacterial Proteins
  • Oligopeptides
  • NAD
  • Oxidoreductases
  • InhA protein, Mycobacterium
  • pyridomycin

Associated data

  • PDB/4BGE
  • PDB/4BGI
  • PDB/4BII