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

  1. Ruben C. Hartkoorn1,
  2. Claudia Sala1,
  3. João Neres1,
  4. Florence Pojer1,
  5. Sophie Magnet1,
  6. Raju Mukherjee1,
  7. Swapna Uplekar1,
  8. Stefanie Boy-Röttger1,
  9. Karl-Heinz Altmann2,
  10. Stewart T. Cole1,*

Article first published online: 17 SEP 2012

DOI: 10.1002/emmm.201201689

Issue

EMBO Molecular Medicine

EMBO Molecular Medicine

Volume 4, Issue 10, pages 1032–1042, October 2012

Additional Information

How to Cite

Hartkoorn, R. C., Sala, C., Neres, J., Pojer, F., Magnet, S., Mukherjee, R., Uplekar, S., Boy-Röttger, S., Altmann, K.-H. and Cole, S. T. (2012), Towards a new tuberculosis drug: pyridomycin – nature's isoniazid. EMBO Mol Med, 4: 1032–1042. doi: 10.1002/emmm.201201689

Author Information

  1. 1

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

  2. 2

    Eidgenössische Technische Hochschule Zürich, Institut für Pharmazeutische Wissenschaften, HCI H 405, Zürich, Switzerland

*Tel: +41 21 693 1851; Fax +41 21 693 1790

Publication History

  1. Issue published online: 2 OCT 2012
  2. Article first published online: 17 SEP 2012
  3. Manuscript Accepted: 30 JUL 2012
  4. Manuscript Revised: 26 JUL 2012
  5. Manuscript Received: 29 JUN 2012

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  • Funded Access

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Keywords:

  • drug discovery;
  • InhA;
  • isoniazid;
  • pyridomycin;
  • tuberculosis

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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