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.
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Authors | Ruben C Hartkoorn, Claudia Sala, João Neres, Florence Pojer, Sophie Magnet, Raju Mukherjee, Swapna Uplekar, Stefanie Boy-Röttger, Karl-Heinz Altmann, Stewart T Cole |
Journal | EMBO molecular medicine
(EMBO Mol Med)
Vol. 4
Issue 10
Pg. 1032-42
(Oct 2012)
ISSN: 1757-4684 [Electronic] England |
PMID | 22987724
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyrights © 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
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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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