Hartkoorn, Ruben C.Sala, ClaudiaNeres, JoaoPojer, FlorenceMagnet, SophieMukherjee, RajuUplekar, SwapnaBoy-Roettger, StefanieAltmann, Karl-HeinzCole, Stewart T.2013-02-272013-02-272013-02-27201210.1002/emmm.201201689https://infoscience.epfl.ch/handle/20.500.14299/89431WOS:000309446200003Tuberculosis, 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.drug discoveryInhAisoniazidpyridomycintuberculosistext::journal::journal article::research article