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

Hartkoorn RC, Sala C, Neres J, Pojer F, Magnet S, Mukherjee R, Uplekar S, Boy-Röttger S, Altmann KH, Cole ST
EMBO Mol Med 4 1032-42 (2012)
Related entries: 4dqu, 4dti

Cited: 95 times
EuropePMC logo PMID: 22987724

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.

Reviews - 4dre mentioned but not cited (1)

  1. In Silico Strategies in Tuberculosis Drug Discovery. Macalino SJY, Billones JB, Organo VG, Carrillo MCO. Molecules 25 E665 (2020)

Articles - 4dre mentioned but not cited (5)

  1. Towards a new tuberculosis drug: pyridomycin - nature's isoniazid. Hartkoorn RC, Sala C, Neres J, Pojer F, Magnet S, Mukherjee R, Uplekar S, Boy-Röttger S, Altmann KH, Cole ST. EMBO Mol Med 4 1032-1042 (2012)
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Reviews citing this publication (40)

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