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

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.
AuthorsRuben C Hartkoorn, Claudia Sala, João Neres, Florence Pojer, Sophie Magnet, Raju Mukherjee, Swapna Uplekar, Stefanie Boy-Röttger, Karl-Heinz Altmann, Stewart T Cole
JournalEMBO molecular medicine (EMBO Mol Med) Vol. 4 Issue 10 Pg. 1032-42 (Oct 2012) ISSN: 1757-4684 [Electronic] England
PMID22987724 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyrights © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.
Chemical References
  • Antitubercular Agents
  • Bacterial Proteins
  • Biological Products
  • Enzyme Inhibitors
  • Mycolic Acids
  • Oligopeptides
  • Oxidoreductases
  • InhA protein, Mycobacterium
  • pyridomycin
Topics
  • Antitubercular Agents (isolation & purification, pharmacology)
  • Bacterial Proteins (antagonists & inhibitors)
  • Biological Products (isolation & purification, pharmacology)
  • Biosynthetic Pathways (drug effects)
  • Drug Resistance, Bacterial
  • Enzyme Inhibitors (isolation & purification, pharmacology)
  • Micromonosporaceae (chemistry)
  • Mutation
  • Mycobacterium tuberculosis (drug effects)
  • Mycolic Acids (metabolism)
  • Oligopeptides (isolation & purification, pharmacology)
  • Oxidoreductases (antagonists & inhibitors)
  • Selection, Genetic

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