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

EMBO Molecular Medicine

Ruben C. Hartkoorn²  Claudia Sala²  João Neres²  Florence Pojer²  Sophie Magnet²  Raju Mukherjee²  Swapna Uplekar²  Stefanie Boy-Röttger²  Karl-Heinz Altmann¹ 

[1] Eidgenössische Technische Hochschule Zürich, Institut für Pharmazeutische Wissenschaften, HCI H 405, Zürich, Switzerland;Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland

关键词: drug discovery;    InhA;    isoniazid;    pyridomycin;    tuberculosis;   

DOI  :  10.1002/emmm.201201689

来源: Wiley

【 摘 要 】

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

【 授权许可】

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