Towards a new tuberculosis drug: pyridomycin - nature's isoniazid

EMBO Mol Med. 2012 Oct;4(10):1032-42. doi: 10.1002/emmm.201201689. Epub 2012 Sep 17.

Abstract

Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development. →See accompanying article http://dx.doi.org/10.1002/emmm.201201811.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / isolation & purification
  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Biological Products / isolation & purification
  • Biological Products / pharmacology*
  • Biosynthetic Pathways / drug effects
  • Drug Resistance, Bacterial
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / pharmacology
  • Micromonosporaceae / chemistry*
  • Mutation
  • Mycobacterium tuberculosis / drug effects*
  • Mycolic Acids / metabolism
  • Oligopeptides / isolation & purification
  • Oligopeptides / pharmacology*
  • Oxidoreductases / antagonists & inhibitors*
  • Selection, Genetic

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Biological Products
  • Enzyme Inhibitors
  • Mycolic Acids
  • Oligopeptides
  • Oxidoreductases
  • InhA protein, Mycobacterium
  • pyridomycin