2013 SwissTB Award
PhD Ruben C. Hartkoorn
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.
Towards a new tuberculosis drug: pyridomycin – nature’s isoniazid.
Ruben C. Hartkoorn1, Claudia Sala1, Joao Neres1, Florence Pojer1, Sophie Magnet1, Raju Mukherjee1, Swapna Uplekar1, Stefanie Boy-Röttger1, Karl-Heinz Altmann2, Stewart T. Cole1
1Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland
2Eidgenössische Technische Hochschule Zürich, Institut für Pharmazeutische Wissenschaften, HCI H 405, Zürich, Switzerland
- EMBO Mol Med 4: 1032-42 (2012)