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

• DOI: 10.1038/nchembio.1405
• Publication Date: 2013-12-01T20:20:41Z
• Authors: Ruben C Hartkoorn; Florence Pojer; Jon A Read; Helen Gingell; João Neres; Oliver P Horlacher; Karl-Heinz Altmann; Stewart T Cole
• Keywords: INHA

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.