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

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

Author information

1
Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.

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.

PMID:
22987724
PMCID:
PMC3491834
DOI:
10.1002/emmm.201201689
[Indexed for MEDLINE]
Free PMC Article

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