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

Autor: Ruben C. Hartkoorn, Claudia Sala, João Neres, Florence Pojer, Sophie Magnet, Raju Mukherjee, Swapna Uplekar, Stefanie Boy‐Röttger, Karl‐Heinz Altmann, Stewart T. Cole
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 4, Iss 10, Pp 1032-1042 (2012)
Druh dokumentu: article
ISSN: 20120168
1757-4676
1757-4684
DOI: 10.1002/emmm.201201689
Popis: 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
Databáze: Directory of Open Access Journals
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